9-Substituted carbacyclin analogs

ABSTRACT

Novel compounds of the following general formula: ##STR1##

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds which are 9-substitutedcarbacyclin analogs, to processes for the preparation of saidcarbacyclin analogs and the use of said analogs as pharmacologicalagents or as intermediates for the preparation of compounds useful aspharmacological agents. This invention also relates to chemicalintermediates for preparing the novel 9-substituted carbacycl incompounds described and claimed herein.

Prostacyclin is an endogenously produced compound in mammalian species,being structurally and biosynthetically related to the prostaglandins(PG's). In particular, prostacyclin exhibits the structure and carbonatom numbering of formula I when the C-5,6 positions are unsaturated.For convenience, prostacyclin is often referred to simply as "PGI₂ ".Carbacyclin, 6a-carba-PGI₂, exhibits the structure and carbon atomnumbering indicated in formula II when the C-5,6 positions areunsaturated. Likewise, for convenience, carbacyclin is referred tosimply as "CBA₂ ".

A stable partially saturated derivative of PGI₂ is PGI₁ or5,6-dihydro-PGI₂ when the C-5,6 positions are saturated, depicted withcarbon atom numbering in formula I when the C-5,6 positions aresaturated. The corresponding 5,6-dihydro-CBA₂ is CBA₁, depicted informula II when the C-5,6 positions are saturated.

As is apparent from inspection of formulas I and II, prostacyclin andcarbacyclin may be trivially named as derivatives of PGF-type compounds,e.g., PGF₂α of formula III. Accordingly, prostacyclin is trivially named9-deoxy-6,9α-epoxy-(5Z)-5,6-didehydro-PGF₁ and carbacyclin is named9-deoxy-6,9α-methano-(5Z)-5,6-didehydro-PGF₁. For description ofprostacyclin and its structural identification, see Johnson, et al,Prostaglandins 12:915 (1976).

In naming the novel compounds of the present invention in general theart-recognized system of nomenclature described by N. A. Nelson, J. Med.Chem. 17:911 (1974) for prostaglandins is followed. As a matter ofconvenience, however, the novel carbacyclin derivatives herein are namedas 6a-carba-prostaglandin I₂ compounds, or as CBA₁ or CBA₂ derivatives.

In the formulas herein, broken line attachments to a ring indicatesubstituents in the "alpha" (α) configuration, i.e., below the plane ofsaid ring. Heavy solid line attachments to a ring indicate substituentsin the "beta" (β) configuration, i.e., above the plane of said ring. Theuse of wavy lines (˜) herein will represent attachment of substituentsin the alpha or beta configuration or attached in a mixture of alpha andbeta configurations. Alternatively wavy lines will represent either an Eor Z geometric isomeric configuration or the mixture thereof. Also,solid and dotted lines used together, as for example, in formulas I andII at C-5,6 positions indicates the presence of either a double bond oralternatively a single bond.

A side chain hydroxy at C-15 in the formulas herein is in the S or Rconfiguration as determined by the Cahn-Ingold-Prelog sequence rules, J.Chem. Ed. 41:16 (1964). See also Nature 212:38 (1966) for discussion ofthe stereochemistry of the prostaglandins which discussion applies tothe novel carbacyclin analogs herein. Molecules of carbacyclin haveseveral centers of asymmetry and therefore can exist in opticallyinactive form or in either of two enantiomeric (optically active) forms,i.e., the dextrorotatory and laveorotatory forms. The racemic form ofcarbacyclin contains equal numbers of both enantiomeric molecules. Forconvenience, reference to carbacyclin or CBA₂ or CBA₁ will refer to theoptically active form thereof.

A formula as drawn herein which depicts a prostacyclin-type product oran intermediate useful in the preparation thereof, represents thatparticular stereoisomer of the prostacyclin-type product which is of thesame relative stereochemical configuration as prostacyclin obtained frommammalian tissues or the particular stereoisomer of the intermediatewhich is useful in preparing the above stereoisomer of the prostacyclintype product. As drawn, formula I corresponds to that of PGI₂endogenously produced in the mammalian species. In particular, refer tothe stereochemical configuration at C-8 (α), C-9 (α), C-11 (α) and C-12(β) of endogenously produced prostacyclin. The mirror image of the aboveformula for prostacyclin represents the other enantiomer.

The term "prostacyclin analog" or "carbacyclin analog" represents thatstereoisomer of a prostacyclin-type product which is of the samerelative stereochemical configuration as prostacyclin obtained frommammalian tissues or a mixture comprising stereoisomer and theenantiomers thereof. In particular, where a formula is used to depict aprostacyclin type product herein, the term "prostacyclin analog" or"carbacyclin analog" refers to the compound of that formula or a mixturecomprising that compound and the enantiomer thereof.

PRIOR ART

Carbacyclin and closely related compounds are known in the art. SeeJapanese Kokia 63,059 and 63,060, also abstracted respectively asDerwent Farmdoc CPI Numbers 48154B/26 and 48155B/26. See also Britishpublished specifications 2,012,265 and German Offenlungsschrift2,900,352, abstracted as Derwent Farmdoc CPI Number 54825B/30. See alsoBritish published applications 2,017,699 and 2,013,661 and U.S. Pat. No.4,238,414. The synthesis of carbacyclin and related compounds is alsoreported in the chemical literature, as follows: Morton, D.R., et al, J.Org. Chem. 44:2880-2887 (1979); Shibasaki, M., et al, Tetrahedron Lett.,433-436 (1979); Kojima, K., et al, Tetrahedron Lett., 3743-3746 (1978);Nicolaou, K.C., et al, J. Chem. Soc. Chemical Communications, 1067-1068(1978); Sugie, A., et. al., Tetrahedron Lett., 2607-2610 (1979);Shibasaki, M., Chem. Lett., 1299-1300 (1979), and Hayashi, M., Chem.Lett., 1437-40 (1979); Aristoff, P.A., J. Org. Chem. 46, 1954-1957(1981); Yamazaki, M., et al, Chem. Lett., 1245-1248 (1981); and Barco,A., et al, J. Org. Chem. 45, 4776-4778 (1980); and Skuballa, W., et al,Angew. Chem. 93, 1080-1081 (1981). 7-Oxo and 7-hydroxy-CBA₂ compoundsare apparently disclosed in U.S. Pat. No. 4,192,891. 19-Hydroxy-CBA₂compounds are disclosed in United States Serial No. 054,811, filed 5July 1979. CBA₂ aromatic esters are disclosed in U.S. Pat. No.4,180,657. 11-Deoxy-Δ¹⁰ -or Δ¹¹ -CBA₂ compounds are described inJapanese Kokai 77/24,865, published 24 Feb. 1979. Related 9β-substitutedcompounds are disclosed in U.S. Pat. Nos. 4,306,075 and 4,306,076.

SUMMARY OF THE INVENTION

The present invention consists of compounds of formula IV wherein R isC₁ -C₄ alkyl; R₃₀ is hydrogen or R₃₀ and R taken together form amethylene moiety, i.e., --CH₂ --;

wherein D is cis-C═C(R₃)--, trans--C═C(R₃)--or >CHCH₂, wherein R₃ ishydrogen or fluoro;

wherein Z is:

(1)--CH₂ --(CH₂)_(f) --C(R₄)₂ --wherein each R₄ is the same and ishydrogen or fluoro, and f is zero, one, 2 or 3;

(2) trans--CH₂ CH═CH--; or

(3) --(Ph)--(CH₂)_(g) --wherein Ph is 1,2--, 1,3--, or 1,4-phenylene andg is zero, one, 2 or 3; with the proviso that when Z is--(Ph)--(CH₂)_(g) --, R₃ is hydrogen;

wherein Q is

(1) --COOR₅, wherein R₅ is

(a) hydrogen,

(b) (C₁ -C₁₂)alkyl,

(c) (C₃ -C₁₀)cycloalkyl,

(d) (C₇ -C₁₂)aralkyl,

(e) phenyl optionally substituted with one, 2 or 3 chloro or (C₁-C₄)alkyl,

(f) phenyl substituted in the para-position with --NHCOR₆, --COR₇,--OC(O)R₈ or --CH═N--NHCONH₂, wherein R₆ is methyl, phenyl,acetamidophenyl, benzamidophenyl or --NH₂ ; R₇ is methyl, phenyl, --NH₂,or methoxy; and R₈ is phenyl or acetamidophenyl;

(g) phthalidyl,

(h) 3-(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-ylP-oxide,

(i)3-(5,5-di(hydroxymethyl)-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-ylP-oxide, or

(j) a pharmacologically acceptable cation;

(2) --CH₂ OH;

(3) --COL₂, wherein L₂ is

(a) an amino group of the formula --NR₉ R₁₀ wherein R₉ is hydrogen or(C₁ -C₁₂)alkyl and R₁₀ is

(i) hydrogen

(ii) (C₁ -C₁₂)alkyl

(iii) (C₃ -C₁₀)cycloalkyl,

(iv) (C₇ -C₁₂)aralkyl

(v) phenyl optionally substituted with one, 2 or 3 chloro, (C₁-C₃)alkyl, hydroxy, carboxy, (C₂ -C₅)alkoxycarbonyl, or nitro,

(vi) (C₂ -C₅)carboxyalkyl,

(vii) (C₂ -C₅)carbamoylalkyl,

(viii) (C₂ -C₅)cyanoalkyl,

(ix) (C₃ -C₆)acetylalkyl,

(x) (C₇ -C₁₂)benzoalkyl, optionally substituted by one, 2, or 3 chloro,(C₁ -C₃)alkyl, hydroxy, (C₁ -C₃)alkoxy, carboxy, (C₂ -C₅)alkoxycarbonyl,or nitro,

(ix) pyridyl, optionally substituted by one, 2, or 3 chloro, (C₁-C₃)alkyl, or (C₁ -C₃)alkoxy,

(xii) (C₆ -C₉)pyridylalkyl optionally substituted by one, 2, or 3chloro, (C₁ -C₃)alkyl, hydroxy, or (C₁ -C₃)alkyl,

(xiii) (C₁ -C₄)hydroxyalkyl,

(xiv) (C₁ -C₄)dihydroxyalkyl,

(xv) (C₁ -C₄)trihydroxyalkyl;

(b) cycloamine selected from the group consisting of pyrolidino,piperidino, morpholino, piperazino, hexamethyleneimino, pyrroline, or3,4-didehydropiperidinyl optionally substituted by one or 2 (C₁-C₁₂)alkyl;

(c) carbonylamino of the formula --NR₁₁ COR₁₀, wherein R₁₁ is hydrogenor (C₁ -C₄)alkyl and R₁₀ is other than hydrogen, but otherwise definedas above;

(d) sulfonylamino of the formula --NR₁₁ SO₂ R₁₀, wherein R₁₁ and R₁₀ aredefined in (c);

(4) --CH₂ NL₃ L₄, wherein L₃ and L₄ are hydrogen or (C₁ -C₄)alkyl, beingthe same or different, or the pharmacologically acceptable acid additionsalts thereof when Q is --CH₂ NL₃ L₄ ; or

(5) --CN;

wherein L is H,H; α--OR₁₂,β--H,β--OR₁₂ ; α--CH₂ OR₁₂, β--H; α--H,β--CH₂OR₁₂ wherein R₁₂ is hydrogen or a hydroxyl protecting group;

wherein Y is trans --CH═CH--, cis--CH═CH--, --CH₂ CH₂ --, or--C.tbd.C--;

wherein M is α--OR₁₂, β--R₁₄ or α-R₁₄, β--OR₁₂ ; wherein R₁₂ is asdefined above, and R₁₄ is hydrogen or methyl;

wherein L₁ is α--R₁₅,β--R₁₆ ; α--R₁₆, β--R₁₅ ; or a mixture thereofwherein R₁₅ and R₁₆ are hydrogen, methyl, or fluoro being the same ordifferent with the proviso that one of R₁₅ and R₁₆ is fluoro only whenthe other of R₁₅ and R₁₆ is hydrogen or fluoro;

wherein R₁₇ is ##STR2## wherein taken together is ##STR3##(2)--C.tbd.C--C_(q) H_(2q) CH₃ wherein q is an integer of from 2 to 6,or

(3) --C_(p) H_(2p) CH═CH₂ wherein p is an integer of from 3 to 7;

and individual optical isomers thereof.

The compounds of Formula V, which are useful as intermediates in thepreparation of the compounds of Formula IV, are also a part of thepresent invention. In Formula V the substituent groups L, Y, M, L₁, R₁₇,s, R₃₀ and R have the same meanings as defined in Formula IV.

In the compounds of the present invention, and as used herein, (---)denotes the α- configuration, ( ) denotes the β-configuration, (˜)denotes α- and/or β- configuration or the E and/or Z isomer.

With regard to the divalent groups described above, i.e., M, L and L₁said divalent groups are defined in terms of an α-substituent and aβ-substituent which means that the α-substituent of the divalent groupis in the alpha configuration with respect to the plane of the C-8 toC-12 cyclopentane ring and the β-substituent is in the betaconfiguration with respect to said cyclopentane ring.

The carbon atoms content of various hydrocarbon containing groups isindicated by a prefix designating the minimum and maximum number ofcarbon atoms in the moiety. For example, in defining the moiety L₂ inthe --COL₂ substituent group the definition (C₁ -C₁₂)alkyl means that L₂can be an alkyl group having from one to 12 carbon atoms. Additionally,any moiety so defined includes straight chain or branched chain groups.Thus (C₁ -C₁₂)alkyl as set forth above includes straight or branchedchain alkyl groups having from 1 to 12 carbon atoms and as additionalillustration, when L₂ represnts, for example, (C₂ -C₅)carboxyalkyl, thealkyl moiety thereof contains from 1 to 4 carbon atoms and is a straightchain or a branched chain alkyl group.

The compounds of the present invention exhibiting the olefinic doublebond at C-5,6 positions are CBA₂ compounds, while compounds which aresaturated at the C-5,6 positions are CBA₁ compounds.

Novel compounds wherein Z is --(Ph)--(CH₂)_(g) -- are designatedinter-o-, inter-m-, or inter-p-phenylene depending on whether theattachment between C-5 and the --(CH₂)_(g) -- moiety is ortho, meta, orpara, respectively. For those compounds wherein g is zero, one or 2, thecarbacyclin analogs so described are further characterized as2,3,4-trinor, 3,4-dinor-, or 4-nor, since in this event the Q-terminatedside chain contains (not including the phenylene) 2, 3, or 4 carbonatoms, respectively, in place of the five carbon atoms contained inPGI₂. The missing carbon atom or atoms are considered to be at the C-4to C-2 positions such that the phenylene is connected to the C-5 and C-1to C-3 positions. Accordingly these compounds are named as 1,5-, 2,5-,and 3,5-inter-phenylene-CBA compounds when g is zero, one, or 2,respectively and when g is 3 the compounds are named as4,5-inter-phenylene-CBA compounds.

Those CBA analogs wherein Z is --CH₂ --(CH₂)_(f) --C(R₄)₂ --wherein R₄is fluoro are characterized as "2,2-difluoro-" compounds. For thosecompounds wherein f is zero, 2, or 3, the carbacyclin analogs sodescribed are further characterized as 2-nor, 2a-homo, or 2a,2b-di-homo,since in this event the Q-terminated side chain contains 4, 6, or 7carbon atoms, respectively, in place of the five carbon atoms containedin PGI₂. The missing carbon atom is condsidered to be at the C-2position such that the C-1 carbon atom is connected to the C-3 position.The additional carbon atom or atoms are considered as though they wereinserted between the C-2 and C-3 positions. Accordingly these additionalcarbon atoms are referred to as C-2a and C-2b, counting from the C-2 tothe C-3 position.

Those CBA analogs wherein Z is trans--CH₂ --CH═CH-- are described as"trans-2,3-didehydro-CBA" compounds.

Those novel compounds where s is 2 are further characterized as7a-homo-CBA compounds by virtue of the cyclohexyl ring replacing theheterocyclic ring of prostacyclin.

Further, all of the novel compounds of the present invention contain asubstituent at the 9β-position and are named as 9β-substituted or6aβ,9β-methano substituted compounds.

When R₃ is fluoro, 5-fluoro-" compounds are described.

When R₁₄ is methyl, the carbacyclin analogs are all named as"15-methyl-" compounds. Further, except for compounds wherein Y iscis--CH═CH--, compounds wherein the M moiety contains an hydroxyl in thebeta configuration are additionally named as "15-epi-" compounds.

For the compounds wherein Y is cis--CH═CH--, then compounds wherein theM moiety contains an hydroxyl in the alpha configuration are named as".-epi-CBA " compounds. For a description of this convention ofnomenclature for identifying C-15 epimers, see U.S. Pat. No. 4,016,184,issued 5 April 1977, particularly columns 24-27 thereof.

The novel carbacyclin analogs herein which contain --(CH₂)₂ --,cis--CH═CH--, or --C.tbd.C-- as the Y moiety, are accordingly referredto as "13,14-dihydro", "cis-13", or "13,14-didehydro" compounds,respectively.

When R₁₇ is ##STR4## the compounds so described are named as17(S),20-dimethyl compounds.

When --C(L₁)--R₁₇ is ##STR5## the compounds are named as"16-(R,S)methyl-18,19-tetradehydro" compounds.

When --C(L₁)R₁₇ is --C.tbd.C--C_(q) H_(2q) CH₃ wherein q is an integerof from 2 to 6 compounds so described are named as "16,17-tetradehydro","16,17-tetradehydro-20-methyl", "16,17-tetradehydro-20-ethyl","16,17-tetrahydro-20-n-propyl" and "16,17-tetrahydro-20-n-butyl"compounds as the integer as represented by q varies from 2 to 6respectively.

When --C(L₁)R₁₇ is --C_(p) H_(2p) CH═CH₂ wherein p is an integer of from3 to 7 the compounds so described are named as "19,20-didehydro","19,20-didehydro-18a, 18b-dihomo", "19,20-didehydro-18a, 18b,18c-tri-homo", "19,20-didehydro-18a, 18b, 18c, 18d-tetrahomo" compoundsas the integer represented by p varies from 3 to 7 respectively.

When at least one of R₁₅ and R₁₆ is not hydrogen then there aredescribed the "16-methyl" (one and only one of R₁₅ and R₁₆ is methyl),"16,16-dimethyl" (R₁₅ and R₁₆ are both methyl), "16-fluoro" (one andonly one of R₁₅ and R₁₆ is fluoro), "16,16-difluoro" (R₁₅ and R₁₆ areboth fluoro) compounds. For those compounds wherein R₁₅ and R₁₆ aredifferent, the carbacyclin analogs so represented contain an asymmetriccarbon atom at C-16. Accordingly, two epimeric configurations arepossible: "(16S)" and "(16R)". Further, there is described by thisinvention the C-16 epimeric mixture: "(16RS)".

When Q is --CH₂ OH, the compounds so described are named as"2-decarboxy-2-hydroxymethyl" compounds.

When Q is --CH₂ NL₃ L₄, the compounds so described are named as"2-decarboxy-2-aminomethyl" or "2-(substituted amino)methyl" compounds.

When Q is --COL₂, the novel compounds herein are named as amides.Further, when Q is --COOR₅ and R₅ is other than hydrogen the novelcompounds herein are named as esters and salts.

When Q is CN the novel compounds herein are named as 2-decarboxy-2-cyanocompounds.

Examples of phenyl esters substituted in the para position (i.e., Q is--COOR₅, R₅ is p-substituted phenyl) include p-acetamidophenyl ester,p-benzamidophenyl ester, p-(p-acetamidobenzamido)phenyl ester,p-(p-benzamidobenzamido)phenyl ester, p-amidocarbonylaminophenyl ester,p-acetylphenyl ester, p-benzoylphenyl ester, p-aminocarbonylphenylester, p-methoxycarbonylphenyl ester, p-benzoyloxyphenyl ester.p-(p-acetamidobenzoyloxy)phenyl ester, and p-hydroxybenzaldehydesemicarbazone ester.

Examples of novel amides herein (i.e., Q is --COL₂) include thefollowing:

(1) Amides within the scope of alkylamino groups of the formula-NR₉ R₁₀are methylamide, ethylamide, n-propylamide, isopropylamide,n-butylamide, n-pentylamide, tert-butylamide, neopentylamide,n-hexylamide, n-heptylamide, n-octylamide, n-nonylamide, n-decylamide,n-undecylamide, and n-dodecylamide, and isomeric forms thereof. Furtherisopropylamide, di-n-butylamide, methylethylamide, di-tert-butylamide,methylpropylamide, methylbutylamide, ethylpropylamide ethylbutylamide,and propylbutylamide. Amides within the scope of cycloalkylamino arecyclopropylamide, cyclobutylamide, cyclopentylamide,2,3-dimethylcyclopentylamide, 2,2-dimethylcyclopentylamide,2-methylcyclopentylamide, 3-tertbutylcyclopentylamide, cyclohexylamide,4-tertbutylcyclohexylamide, 3-isopropylcyclohexlamide,2,2-dimethylcyclohexlamide, cycloheptylamide, cyclooctylamide,cyclononylamide, cyclodecylamide, N-methyl-N-cyclobutylamide,N-methyl-N-cyclopentylamide, N-methyl-N-cyclohexylamide,N-ethyl-N-cyclopentylamide, and N-ethyl-N-cyclohexylamide. Amides withinthe scope of aralkylamino are benzylamide, 2-phenylethylamide, andN-methyl-N benzyl-amide. Amides within the scope of substitutedphenylamide are p-chloroanilide, m-chloroanilide, 2,4-dichloroanilide,2,4,6-trichloroanilide, m-nitroanilide, p-nitroanilide,p-methoxyanilide, 3,4-dimethoxyanilide, 3,4,5-trimethoxyanilide,p-hydroxymethylanilide, p-methylanilide, m-methyl anilide,p-ethylanilide, t-butylanilide, p-carboxyanilide, p-methoxycarbonylanilide, p-carboxyanilide and o-hydroxyanilide. Amides within the scopeof carboxyalkylamino are carboxyethylamide, carboxypropylamide andcarboxymethylamide, carboxybutylamide. Amides within the scope ofcarbamoylalkylamino are carbamoylmethylamide, carbamoylethylamide,carbamoylpropylamide, and carbamoylbutylamide. Amides within the scopeof cyanoalkylamino are cyanomethylamide, cyanoethylamide,cyanopropylamide, and cyanobutylamide. Amides within the scope ofacetylalkylamino are acetylmethylamide, acetylethylamide,acetylpropylamide, and acetylbutylamide. Amides within the scope ofbenzoylalkylamino are benzoylmethylamide, benzoylethylamide,benzoylpropylamide, and benzoylbutylamide. Amides within the scope ofsubstituted benzoylalkylamino are p-chlorobenzoylmethylamide,m-chlorobenzoylmethylamide, 2,4-dichlorobenzoylmethylamide,2,4,6-trichlorobenzoylmethylamide, m-nitrobenzoylmethylamide,p-nitrobenzoylmethylamide, p-methoxybenzoylmethylamide, 2,4-dimethoxybenzoylmethylamide, 3,4,5-trimethoxybenzoylmethylamide,p-hydroxymethylbenzoylmethylamide, p-methylbenzoylmethylamide,m-methylbenzoylmethylamide, p-ethylbenzoylmethylamide,t-butylbenzoylmethylamide, p-carboxybenzoylmethylamide,m-methoxycarbonylbenzoylmethylamide, o-carboxybenzoylmethylamide,o-hydroxybenzoylmethylamide, p-chlorobenzoylethylamide,m-chlorobenzoylethylamide, 2,4-dichlorobenzoylethylamide,2,4,6-trichlorobenzoylethylamide, m-nitrobenzoylethylamide,p-nitrobenzoylethylamide, p-methoxybenzoylethylamide,p-methoxybenzoylethylamide, 2,4-dimethoxybenzoylethylamide,3,4,5trimethoxybenzoylethylamide, p-hydroxymethylbenzoylethylamide,p-methylbenzoylethylamide, m-methylbenzoylethylamide,p-ethylbenzoylethylamide, t-butylbenzoylethylamide,p-carboxybenzoylethylamide, m-methoxycarbonylbenzoylethylamide,o-carboxybenzoylethylamide, o-hydroxybenzoylethylamide,p-chlorobenzoylpropylamide, m-chlorobenzoylpropylamide,2,4-dichlorobenzoylpropylamide, 2,4,6-trichlorobenzoylpropylamide,m-nitrobenzoylpropylamide, p-nitrobenzoylpropylamide,p-methoxybenzoylpropylamide, 2,4-dimethoxybenzoylpropylamide,3,4,5-trimethyoxybenzoylpropylamide, p-hydroxymethylbenzoylpropylamide,p-methylbenzoylpropylamide, m-methylbenzoylpropylamide,p-ethylbenzoylpropylamide, t-butylbenzoylpropylamide,p-carboxybenzoylpropylamide, m-methoxycarbonylbenzoylpropylamide,o-carboxybenzoylpropylamide, o-hydroxybenzoylpropylamide,p-chlorobenzoylbutylamide, m-chlorobenzoylbutylamide,2,4-dichlorobenzoylbutylamide, 2,4,6-trichlorobenzoylbutylamide,m-nitrobenzoylmethylamide, p-nitrobenzoylbutylamide,p-methoxybenzoylbutylamide, 2,4-dimethoxybenzoylbutylamide,3,4,5-trimethoxybenzoylbutylamide, p-hydroxymethylbenzoylbutylamide,p-methylbenzoylbutyamide, m-methylbenzoylbutylamide,p-ethylbenzoylbutylamide, m-methylbenzoylbutylamide,p-ethylbenzoylbutylamide, t-butylbenzoylbutylamide,p-carboxybenzoylbutylamide, m-methoxycarbonylbenzoylbutylamide,o-carboxybenzoylbutylamide, o-hydroxybenzoylmethylamide. Amides withinthe scope of pyridylamino are α-pyridylamide, β-pyridylamide, andγ-pyridylamide. Amides within the scope of substituted pyridylamino are4-methyl-α-pyridylamide, 4-methyl-β-pyridylamide,4-chloro-α-pyridylamide, and 4-chloro-β-pyridylamide. Amides within thescope of pyridylalkylamino are α-pyridylmethylamide,β-pyridylmethylamide, γ-pyridylmethylamide, α-pyridylethylamide,β-pyridylethylamide, γ-pyridylethylamide, α-pyridylpropylamide,β-pyridylpropylamide, γ-pyridylpropylamide, α-pyridylbutylamide,β-pyridylbutylamide, and γ-pyridylbutylamide. Amides within the scope ofsubstituted pyridylalkylamido are 4-methyl-α-pyridylmethylamide,4-methyl-β-pyridylmethylamide, 4-chloro-α-pyridylmethylamide,4-chloro-β-pyridylmethyl-amide, 4-methyl-α-pyridylpropylamide,4-methyl-β-pyridylpropylamide, 4-chloro-α-pyridylpropylamide,4-chloro-β-pyridylpropylamide, 4-methyl-α-pyridylbutylamide,4-methyl-β-pyridylbutylamide, 4-chloro-α-pyridylbutylamide,4-chloro-β-pyridylbutylamide, 4-chloro-γ-pyridylbutylamide. Amideswithin the scope of hydroxyalkylamino are hydroxymethylamide,β-hydroxyethylamide, β-hydroxypropylamide, γ-hydroxypropylamide,1-(hydroxymethyl)ethyl-amide, 1-(hydroxymethyl)propylamide,(2-hydroxymethyl)propylamide, and α,α,-dimethyl-hydroxyethylamide.Amides within the scope of dihydroxyalkylamino are dihydroxymethylamide,β,γ-dihydroxypropylamide, 1-(hydroxymethyl)2-hydroxymethylamide, β,γ-dihydroxybutylamide, β,δ-dihydroxybutyl-amide, γ,δ-dihydroxybutylamide,and 1,1-bis(hydroxymethyl)ethylamide. Amides within the scope oftrihydroxyalkylamino are tris(hydroxy-methyl)methylamide and1,3-dihydroxy-2-hydroxymethylpropylamide.

(2) Amides within the scope of cycloamino groups described above arepyrrolidylamide, piperidylamide, morpholinylamide,hexamethyleneiminylamide, piperazinylamide, pyrrolinylamide, and3,4-didehydropiperidinylamide each of which may be optionallysubstituted with one or 2 straight or branched alkyl chains having from1 to 12 carbon atoms.

(3) Amides within the scope of carbonylamino of the formula --NR₁₁ COR₁₀are methylcarbonylamide, ethylcarbonylamide, phenylcarbonylamide, andbenzylcarbonylamide.

(4) Amides within the scope of sulfonylamino of the formula --NR₁₁ COR₁₀are methysulfonylamide, ethylsulfonylamide, phenylsulfonylamide,p-tolylsulfonylamide, benzylsulfonylamide.

Examples of alkyl of one to 12 carbon atoms, inclusive, are methyl,ethyl, propyl, isopropyl, isobutyl, tert-butyl, isopentyl, neopentyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,isomeric forms thereof.

Examples of (C₃ -C₁₀)cycloalkyl which includes alkyl-substitutedcycloalkyl, are cyclopropyl, 2-methylcyclopropyl,2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl,cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,2-pentylcyclopentyl, 3-tertbutylcyclopentyl, cyclohexyl,4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

Examples of (C₇ -C₁₂)aralkyl are benzyl, 2-phenylethyl, 1-phenylethyl,2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-(1-naphthylethyl), and1-(2-naphthylmethyl).

Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4carbon atoms, inclsive, are p-chlorophenyl, m-chlorophenyl),2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl,4-chloro-2methylphenyl, and 2,4-dichloro-3-methylphenyl.

The terms phthalidyl;3-(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-yl P-oxide;and 3-(5,5-di(hydroxymethyl)-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-yl P-oxide; which R₅ mayrepresent in the --COOR₅ group mean the following respective moieties(a), (b) and (c): ##STR6##

As indicated hereinabove R₁₂ is hydrogen or a protecting group. Thoseprotective groups within the scope of R₁₂ are any group which replaces ahydroxy hydrogen and is neither attacked by nor is reactive to thereagents used in the transformations used herein as a hydroxy is andwhich is subsequently replaceable by hydrolysis with hydrogen in thepreparation of the carbacyclin-type compounds. Several such protectivegroups are known in the art, e.g., tetrahydropyranyl and substitutedtetrahydropyranyl. See for reference E. J. Corey, Proceedings of theRobert A. Welch Foundation Conferences on Chemical Research, XII OrganicSynthesis, pp. 51-79 (1969). Those blocking groups which have been founduseful include:

(a) tetrahydropyranyl;

(b) tetrahydrofuranyl;

(c) a group of the formula --C(OR₂₄)(R₁₈)--CH(R₁₉)(R₂₀), wherein R₂₄ isalkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbonatoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl orphenyl substituted with one to 3 alkyl of one to 4 carbon atoms,inclusive, wherein R₁₈ and R₁₉ are alkyl of one to 4 carbon atoms,inclusive, phenyl, phenyl substituted with one, 2 or 3 alkyl of one to 4carbon atoms, inclusive, or when R₁₈ and R₁₉ are taken together--(CH₂)_(a) -- or when R₁₈ and R₁₉ are taken together to form--(CH₂)_(b) --O--(CH₂)_(c), wherein a is 3, 4, or 5 and b is one, 2, or3, and c is one, 2, or 3, with the proviso that b plus c is 2, 3, or 4,with the further proviso that R₁₈ and R₁₉ may be the same or different,and wherein R₂₀ is hydrogen or phenyl; and

(d) silyl groups according to R₂₁, as qualified hereinafter.

When the protective group R₁₂ is tetrahydropyranyl, thetetrahydropyranyl ether derivative of any hydroxy moieties of theCBA-type intermediates herein is obtained by reaction of thehydroxy-containing compound with 2,3-hydropyran in an inert solvent,e.g., dichloromethane, in the presence of an acid condensing agent suchas p-toluenesulfonic acid or pyridine hydrochloride. The dihydropyran isused in large stoichiometric excess, preferably 4 to 100 times thestoichiometric amount. The reaction is normally complete in less than anhour at 20°-50° C.

When the R₁₂ protective group is tetrahydrofuranyl, 2,3-dihydrofuran isused, as described in the preceding paragraph, in place of the2,3-dihydropyran.

When the R₁₂ protective group is of the formula--C(OR₂₄)(R₁₈)--CH(R₁₉)(R₂₀), wherein R₂₄, R₁₈, R₁₉, and R₂₀ are asdefined above; a vinyl ether or an unsaturated cyclic or heterocycliccompound, e.g., 1-cyclohexen-1-yl methyl ether, or5,6-dihydro-4-methoxy-2H-pyran is employed. See C. B. Reese, et al., J.American Chemical Society 89, 3366 (1967). The reaction conditions forsuch vinyl ethers and unsaturated compounds are similar to those fordihydropyran above.

R₂₁ is a silyl protective group of the formula --Si(G₁)₃. In some cases,such silylations are general, in that they silylate all hydroxyls of amolecule, while in other cases they are selective, in that while one ormore hydroxyls are silylated, at least one other hydroxyl remainsunaffected. For any of these silylations, silyl groups within the scopeof --Si(G₁)₃ include trimethylsilyl, dimethylphenylsilyl,triphenylsilyl, t-butyldimethylsilyl, or methylphenylbenzylsilyl. Withregard to G₁, examples of alkyl are methyl, ethyl, propyl, isobutyl,butyl, sec-butyl, tert-butyl, pentyl, and the like. Examples of aralkylare benzyl, phenethyl, α-phenylethyl, 3-phenylpropyl, α-naphthylmethyl,and 2-(α-naphthyl)ethyl. Examples of phenyl substituted with halo oralkyl are p-chlorophenyl, m-fluorophenyl, o-tolyl, 2,4-dichlorophenyl,p-tert-butylphenyl, 4-chloro-2-methylphenyl, and2,4-dichloro-3-methylphenyl.

These silyl groups are known in the art. See for example, Pierce"Silylation of Organic Compounds," Pierce Chemical Company, Rockford,Ill. (1968). When silylated products of the charts below are intended tobe subjected to chromatographic purification, then the use of silylgroups known to be unstable to chromatography (e.g. trimethylsilyl) isto be avoided. Further, when silyl groups are to be introducedselectively, silylating agents which are readily available and known tobe useful in selective silylations are employed. For example,t-butyldimethylsilyl groups are employed when selective introduction isrequired. Further, when silyl groups are to be selectively hydrolyzed inthe presence of protective groups according to R₁₂ or acyl protectivegroups, then the use of silyl groups which are readily available andknown to be easily hydrolyzable with tetra-n-butylammonium fluoride areemployed. A particularly useful silyl group for this purpose ist-butyldimethylsilyl, while other silyl groups (e.g. trimethylsilyl) arenot employed when selective introduction and/or hydrolysis is required.

The protective groups as defined by R₁₂ are otherwise removed by mildacidic hydrolysis. For example, by reaction with (1) hydrochloric acidin methanol; (2) a mixture of acetic acid, water, and tetrahydrofuran,or (3) aqueous citric acid or aqueous phosphoric acid intetrahydrofuran, at temperatures below 55° C., hydrolysis of theblocking group is achieved.

R₁₃ is a hydroxyl protective group, as indicated above. As such, R₁₃ maybe an acyl protective group according to R₂₂ as defined below, an acidhydrolyzable protective group according to R₁₂ as defined above, a silylprotective group according to R₂₁ as defined above, or an arylmethylprotecting group as defined below as substituent R₁.

Acyl protecting groups according to R₂₂ include:

(a) benzoyl;

(b) benzoyl substituted with one to 5 alkyl of one to 4 carbon atoms,inclusive, or phenylalkyl of 7 to 12 carbon atoms, inclusive, or nitro,with the proviso that not more than two substituents are other thanalkyl, and that the total number of carbon atoms in the substituentsdoes not exceed 10 carbon atoms, with the further proviso that thesubstituents are the same or different;

(c) benzoyl subsituted with alkoxycarbonyl of 2 to 5 carbon atoms,inclusive;

(d) naphthoyl;

(e) naphthoyl substituted with one to 9, inclusive, alkyl of one to 4carbon atoms, inclusive, phenylalkyl of 7 to 10 carbon atoms, inclusive,or nitro, with the proviso that not more than two substituents on eitherof the fused aromatic rings are other than alkyl and that the totalnumber of carbon atoms in the substituents on either of the fusedaromatic rings does not exceed 10 carbon atoms, with the futher provisothat the various substituents are the same or different; or

(f) alkanoyl of 2 to 12 carbon atoms, inclusive.

In preparing these acyl derivatives of a hydroxy-containing compoundherein, methods generally known in the art are employed. Thus, forexample, an aromatic acid of the formula R₂₂ OH, wherein R₂₂ is asdefined above (e.g., R₂₂ OH is benzoic acid), is reacted with thehydroxy-containing compound in the presence of a dehydrating agent, e.g.p-toluensulfonyl chloride or dicyclohexylcarbodiimide; or alternativelyan anhydride of the aromatic acid of the formula (R₂₂)OH, e.g., benzoicanhydride, is used.

Preferably, however, the process described in the above paragraphproceeds by use of the appropriate acyl halide, e.g., R₂₂ Hal, whereinHal is chloro, bromo, or iodo. For example, benzoyl chloride is reactedwith the hydroxyl-containing compound in the presence of a hydrogenchloride scavenger, e.g. a tertiary amine such as pyridine,triethylamine or the like. The reaction is carried out under a varietyof conditions, using procedures generally known in the art. Generallymild conditions are employed: 0°-60° C., contacting the reactants in aliquid medium (e.g., excess pyridine or an inert solvent such asbenzene, toluene, or chloroform). The acylating agent is used either instoichiometric amount or in substantial stoichiometric excess.

As examples of R₂₂, the following compounds are available as acids (R₂₂OH), (R₂₂)₂ O, or acyl chlorides (R₂₂ Cl): benzoyl; substituted benzoyl,e.g., (2-, 3-, or 4-)methylbenzoyl, (2-, 3-, or 4-)ethylbenzoyl, (2-,3-, or 4-)isopropylbenzoyl, (2-, 3-, or 4-)tertbutylbenzoyl,2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl,2,4,6-trimethylbenzoyl, pentamethylbenzoyl, phenyl(2-, 3-, or 4-)toluyl,(2-, 3-, or 4-)phenethylbenzoyl, (2`-, 3-, or 4-)nitrobenzoyl, (2,4,2,5-, or 2,3-)dinitrobenzoyl, 2,3-dimethyl-2-nitrobenzoyl,4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenylethylbenzoyl,3-nitro-2-phenethylbenzoyl, 2-nitro-6-phenethylbenzoyl,3-nitro-2-phenethylbenzoyl; mono esterified phthaloyl, isophthaloyl, orterephthaloyl; 1- or 2-naphthoyl; subsituted naphthoyl, e.g., (2-, 3-,4-, 5-, 6-, or 7-)methyl-1-naphthoyl, (2- or 4-)ethyl-1-naphthoyl,2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-naphthoyl,6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5-, or8-)-nitro-1-naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7-, or8-)-methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or8-)nitro-2-naphthoyl and acetyl.

There may be employed, therefore, benzoyl chloride, 4-nitrobenzoylchloride, 3,5-dinitrobenzoyl chloride, or the like, i.e. R₂₂ Clcompounds corresponding to the above R₂₂ groups. If the acyl chloride isnot available, it is prepared from the corresponding acid and phosphoruspentachloride as is known in the art. It is preferred that the R₂₂ OH,(R₂₂)₂ O, or R₂₂ Cl reactant does not have bulky hinderingsubstitutents, e.g. tert-butyl on both of the ring carbon atoms adjacentto the carbonyl attaching site.

The acyl protective groups, according to R₂₂, are removed bydeacylation. Alkali metal carbonate or hydroxide are employedeffectively at ambient temperature for this purpose. For example,potassium carbonate or hydroxide in aqueous methanol at about 25° C. isadvantageously employed.

R₁ is any arylmethyl group which replaces the hydroxy hydrogen of theintermediates in the preparation of the various CBA analogs herein whichis subsequently replaceable by hydrogen in the processes herein forpreparation of these respective carbacyclin analogs, being stable withrespect to the various reactions to which R₁₃ -containing compounds aresubjected and being introduced and subsequently removed byhydrogenolysis or by treatment with liquid ammonia in an ether solventsuch as diethyl ether in the presence of a strong base such as an alkyllithium.

Examples of arylmethyl protecting groups are

(a) benzyl;

(b) benzyl substituted by one to 5 alkyl of one to 4 carbon atomsinclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12carbon atoms, inclusive, with the further proviso that the varioussubstituents are the same or different;

(c) benzhydryl;

(d) benzhydryl substituted by one to 10 alkyl of one to 4 carbon atoms,inclusive, chloro, bromo, iodo, fluoro, nitro, phenalkyl of 7 to 12carbon atoms, inclusive, with the further proviso that the varioussubstituents are the same or different on each of the aromatic rings;

(e) trityl;

(f) trityl substituted by one to 15 alkyl of one to 4 carbon atoms,inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12carbon atoms, inclusive, with the further proviso that the varioussubstituents are the same or different on each of the aromatic rings.

The introduction of such ether linkages to the hydroxy-containingcompounds herein, particularly the benzyl or substituted benzyl etherproceeds by methods known in the art, for example by reaction of thehydroxy-containing compound with the benzyl or substituted benzyl halide(chloride, bromide, or iodide) corresponding to the desired ether. Thisreaction proceeds in the presence of an appropriate condensing agent(e.g., silver oxide). The mixture is stirred and heated to 50°-80° C.Reaction times of 4 to 20 hr are ordinarily sufficient.

The novel CBA analogs disclosed herein wherein R₁₂ is hydrogen producecertain prostacyclin-like pharmacological responses.

Accordingly, the novel formula IV wherein R₁₂ is hydrogen are used asagents in the study, prevention, control, and treatment of diseases, andother undesirable physiological conditions, in mammals, particularlyhumans, valuable domestic animals, pets, zoological specimens, andlaboratory animals (e.g., mice, rats, rabbits and monkeys). Inparticular, these compounds are useful as anti-ulcer agents andanti-asthma agents, and as antithrombotic agents as indicated below. Thecompounds of Formula IV wherein R₁₂ is hydrogen are particularly usefulin that said compounds possess an improved ratio of platelet aggregationto blood pressure lowering effects as compared to closely relatedcompounds.

(a) Platelet Aggregation Inhibition

The compounds of formula IV wherein R₁₂ is hydrogen are useful wheneverit is desired to inhibit platelet aggregation, to reduce the adhesivecharacter of platelets, or to remove or prevent the formation of thrombiin mammals, including man. For example, these compounds are useful inthe treatment and prevention of myocardial infarcts, to treat andprevent post-operative thrombosis, to promote patency of vascular graftsfollowing surgery, to treat peripheral vascular diseases, and to treatconditions such as atherosclerosis, arteriosclerosis, blood clottingdefects due to lipemia, and other clinical conditions in which theunderlying etiology is associated with lipid imbalance orhyperlipidemia. Other in vivo applications include geriatric patients toprevent cerebral ischemic attacks and long term prophylaxis followingmyocardial infarcts and strokes. For these purposes, these compounds areadministered systemically, e.g., intravenously, subcutaneously,intramuscularly, and in the form of sterile implants for prolongedaction. For rapid response, especially in emergency situations, theintravenous route of administration is preferred.

The preferred dosage route for these compounds is oral, although othernon-parenteral routes (e.g., buccal, rectal, sublingual) are likewiseemployed in preference to parenteral routes. Oral dosage forms areconventionally formulated as, e.g., tablets or capsules and administered2-4 times daily. Doses in the range of about 0.05 to 100 mg per kg ofbody weight per day are effective in treating the aforedescribedconditions associated with the inhibition of platelet aggregation. Dosesin the range about 0.01 to about 10 mg per kg of body weight per day arepreferred, the exact dose depending on the age, weight, and condition ofthe patient or animal, and on the frequency and route of administration.

The addition of these compounds to whole blood provides in vitroapplications such as storage of whole blood to be used in heart-lungmachines. Additionally whole blood containing these compounds can becirculated through organs, e.g., heart and kidneys, which have beenremoved from a donor prior to transplant. They are also useful inpreparing platelet rich concentrates for use in treatingthrombocytopenia, chemotherapy, and radiation therapy. In vitroapplications utilize a dose of 0.001-1.0 μg per ml of whole blood. Thesecompounds, i.e., the compounds of formula IV wherein R₂ is hydrogen areuseful in the treatment of peripheral vascular dieases, in the samemanner as described in U.S. Pat. No. 4,103,026.

(b) Gastric Secretion Reduction

Compounds of Formula IV wherein R₁₂ is hydrogen are useful in mammals,including man and certain useful animals, e.g., dogs and pigs, to reduceand control gastric secretion, thereby to reduce or avoidgastrointestinal ulcer formation, and accelerate the healing of suchulcers already present in the gastrointestinal tract. For this purpose,these compounds are injected or infused intravenously, subcutaneously,or intramuscularly in an infusion dose range of about 0.1 μg to about 20μg per kg of body weight per minute, or in a total daily dose byinjection or infusion in the range about 0.01 to about 10 mg per kg ofbody weight per day, the exact dose depending on the age, weight, andcondition of the patient or animal, and on the frequency and route ofadministration.

Preferably, however, these novel compounds are administered orally or byother non-parenteral routes. As employed orally, one to 6administrations daily in a dosage range of about 1.0 to 100 mg per kg ofbody weight per day is employed. Once healing of the ulcers has beenaccomplished the maintenance dosage required to prevent recurrence isadjusted downward so long as the patient or animals remainsasymptomatic.

(c) NOSAC-Induced Lesion Inhibition

Compounds of Formula IV wherein R₁₂ is hydrogen are also useful inreducing the undesirable gastrointestinal effects resulting from systemadministration of the anti-inflammatory prostaglandin synthetaseinhibitors, and are useful for that purpse of concomitant administrationof said compounds of Formula IV and the anti-inflammatory prostaglandinsynthetase inhibitor. See Partridge, et al., U.S. Pat. No. 3,781,429,for a disclosure that the ulcerogenic effect induced by certainnon-steroidal anti-inflammatory agents in rats is inhibited byconcomitant oral administration of certain prostaglandins of the Eseries. Accordingly these novel Formula IV compounds are useful, forexample, in inducing the undesirable gastrointestinal effects resultingfrom systemic administration of known prostaglandin synthetaseinhibitors, e.g., indomethacin, phenylbutazone, and aspirin, in the samemanner as described by Partridge, et al, for the PGE compounds in U.S.Pat. No. 3,781,429.

The anti-inflammatory synthetase inhibitor, for example, indomethacin,aspirin, or phenylbutazone is administrated in any of the ways known inthe art to alleviate an inflammatory conditions, for example, in anydosage regimen and by any of the known routes of systemicadministration.

(d) Bronchodilation (Anti-asthma)

The compounds of Formula IV wherein R₁₂ is hydrogen are also useful inthe treatment of asthma. For example, these compounds are useful asbronchodilators or as inhibitors of mediator-inducedbronchoconstriction, such as SRS-A, and histamine which are releasedfrom cells activated by an antigen-antibody complex. Thus, thesecompounds control spasm and facilitate breathing in conditions such asbronchial bronchitis, bronchiectasis, pneumonia and emphysema. For thesepurposes, these compounds are administered in a variety of dosage forms,e.g., orally in the form of tablets, capsules, or liquids; rectally inthe form of suppositories, parenterally, subcutaneously, orintramuscularly, with intravenous administration being preferred inemergency situations; by inhalation in the form of aerosols or solutionsfor nebulizers; or by insufflation in the form of powder. Doses in therange of about 0.01 to 5 mg per kg of body weight are used to 1 to 4times a day, the exact dose depending on the age, weight, and conditionof the patient and on the frequency and route of administration. For theabove use Formula IV compounds can be combined advantageously with otheranti-asthmatic agents, such as sympathomimetics (isoproterenol,phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline andaminophylline); and corticosteroids (ACTH and prednisolone).

The pharmacologically useful Formula IV compounds are effectivelyadministered to human asthma patients by oral inhalation or by aerosolinhalation. For administration by the oral inhalation route withconventional nebulizers or by oxygen aerosolization it is convenient toprovide the instant active ingredient in dilute solution, preferably atconcentrations of about one part of medicament to from about 100 to 200parts by weight of total solution. Entirely conventional additives maybe employed to stabilize these solutions or to provide isotonic media,for example, sodium chloride, sodium citrate, citric acid, sodiumbisulfite, and the like can be employed. For administration as aself-propelled dosage unit for administering the active ingredient inaerosol form suitable for inhalation therapy the composition cancomprise the active ingredient suspended in an inert propellant (such asa mixture of dichlorodifluoromethane and dichlorotetrafluoroethane)together with a co-solvent, such as ethanol, flavoring materials andstabilizers. Suitable means to employ the aerosol inhalation therapytechnique are described fully in U.S. Pat. No. 3,868,691, for example.

When Q is --COOR₅, the novel Formula IV compounds so described are usedfor the purposes described above in the free acid form, in ester form,or in pharmacologically acceptable salt form. When the ester form isused, the ester is any of those within the above definition of R₅.However, it is preferred that the ester by alkyl of one to 12 carbonatoms, inclusive. Of the alkyl esters, methyl and ethyl are especiallypreferred for optimum absorption of the compound by the body orexperimental animal system; and straight-chain octyl, nonyl, decyl,undecyl, and dodecyl are especially preferred for prolonged activity.

Pharmacologically acceptable salts of the novel compounds of Formula IVfor the purposes described above are those with pharmacologicallyacceptable metal cations, ammonia, amine cations, or quaternary ammoniuncations. Illustrative pharmacological acceptable cations which R₅ mayrepresent are the following.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium, and potassium, and from the alkalineearth metals, e.g., magnesium and calcium, although cationic forms ofother metals, e.g., aluminum, zinc, and iron are within the scope ofthis invention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, and tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine,ethylenediamine, diethylenetriamine, adamantylamine, and the likealiphatic, cycloaliphatic, araliphatic amines containing up to andincluding about 18 carbon atoms, as well as heterocyclic amines, e.g.,piperidine, morpholine, pyrrolidine, piperazine, and lower-alkylderivates thereto, e.g., 1- methylpiperidine, 4-ethylmorpholine,1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine,2-methylpiperidine, and the like as well as amines containingwater-solubilizing or hydropholic groups, e.g, mono-, di-, andtriethanolamine, ethyldiethanolamine, N-butylethanolamine,2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris(hydroxymethyl) aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)-diethanolamine, glactamine,N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like. Further useful amines salts of thebasic amino acid salts, e.g., lysine and arginine.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

When Q is --CH₂ NL₃ L₄, the Formula IV compounds so described are usedfor the purposes described in either free base or pharmacologicallyacceptable acid addition salt form.

The acid addition salts of the 2-decarboxy-2-aminomethyl- or2-(substituted aminomethyl)-Formula IV compounds provided by thisinvention are, for example, the hydrochlorides, hydrobromides,hydriodides, sulfates, phosphates, cyclohexanesulfamates,methanesulfonates, ethanesulfonates, benzenesulfonates,toluenesulfonates and the like, prepared by reacting the appropriatecompound of Formula IV with the stoichiometric amount of the acidcorresponding to the pharmacologically acceptable acid addition salts.

To obtain the optimum combination of biological response specificity,potency, and duration of activity, certain compounds within the scope ofthis invention are preferred. Preferred compounds of the presentinvention are the CBA₂ analogs, i.e., the copounds of Formula IV whereinthe C-5,6 position is unsaturated, and of these compounds those whereinY is --CH₂ CH₂ --, --C.tbd.C-- or trans --CH═CH-- and/or Q is --COOR₅ or--COL₂ are preferred especially when R₅ is hydrogen, methyl, ethyl, or apharmacologically acceptable cation such as sodium, and when each of R₉and R₁₀ of the L₂ substituent moiety is hydrogen. Of these preferredcompounds those wherein R₃ is hydrogen are more preferred. To furthercharacterize are preferred embodiments of the present invention,compounds of Formula IV wherein ##STR7## are more preferred particularlywhen R₃₀ and R taken together are --CH₂ --. Compounds wherein R ismethyl are also more particularly preferred also.

Preferred for biological potency are formula IV CBA₂ analogs exhibitingthe same C-5 isomeric configuration as CBA₂ itself. As is apparent fromthe foregoing as compounds which satisfy more of the above preferencessaid compounds are more preferred.

The carbacyclin analogs of the present invention as represented byFormula IV are prepared by various procedures which are all generallyknown in the art. The various charts provided herein are useful inillustrating the preparation of the compounds.

In each of the charts the substituent groups s, L, M, Y, L₁, R₁₇, Q, R,R₃₀, and g have the meanings defined in Formula IV, and R₂₁ is a silylprotecting group as defined hereinabove. The group Z₁ has the samemeaning as Z except Z₁ other than --(Ph)--(CH₂)_(g) --. The group Q' hasthe same meaning as Q except Q' is not --COOH.

As indicated hereinabove the hydroxyl groups at positions C-11 and C-15of the compounds of the present invention may be protected by variousgroups generally employed in the art and protection of the hydroxylfunctions is generally desirable or necessary during the preparation ofthe compounds. Although any of the various protecting groups describedherein may be employed those preferred are tetrahydropyranyl (THP) andtert-butyldimethylsilyl. Particularly, THP is a preferred protectinggroup during the various reactions required to add the side chains andt-butyldimethylsilyl is a preferred group to employ during separation ofthe isomers. Of course it may be useful or desirable to utilizeprotecting groups which may be selectively hydrolyzed.

Also, it will be apparent that in the preparation of the compounds the5(E) and 5(A) isomers generally may be separated when the C-11 and C-15hydroxyl groups are either protected or are unprotected. However, it hasbeen found that protection of these hydroxyl groups with, e.g.,tert-butyldimethyl silyl often facilitates clean separation of theisomers in high yield. Separation of the 5(E) and 5(Z) isomers isachieved by conventional means, typically column chromatography isemployed.

Referring to Chart A wherein there is represented schematically thepreparation of 9β-alkylC₁ -C₄ and 6a,9-methano-substituted compounds(Formula A-2) which are novel intermediates useful in preparing theFormula IV compounds and which are regarded as part of the presentinvention. The enones of Formula A-1 are known in the art or areprepared by procedures known in the art as generally describedhereinbelow.

To obtain the 9β-alkylC₁ -C₄ substituted intermediates of Formula A-2enones of Formula A-1 are treated with lithium dialkyl cuprate in, e.g.,diethyl ether. The appropriate lithium dialkyl cuprate is prepared byconventional means, e.g., by reaction of anhydrous copper iodide indiethyl ether with an alkyllithium in diethyl ether. To obtain the6a,9-methano substituted compounds of Formula A-3 the enones of FormulaA-1 are treated with the anion of trimethyloxosulfonium iodide asgenerally described by E. J. Corey, J. Am. Chem. Soc. 87, 1353 (1965).The anion is conveniently generated by treatment oftrimethyloxosulfonium iodide in sodium hydride. Alternatively, theintermediates of Formula A-3 are prepared by treating the corresponding9β-CH₂ OH derivative with an excess (e.g., two equivalents) ofp-toluenesulfonyl chloride or methanesulfonyl chloride in a tertiaryamine base to yield the corresponding tosylate or mesylate derivatives.The tosylate or mesylate derivatives are treated with a base such aspotassium tert-butoxide to give the 6a,9-methano intermediates ofFormula A-3. To obtain the 9β-CH₂ OH compounds, compounds of Formula A-1are subjected to photochemical addition of methanol in a manneranalogous to the procedure described by G. L. Bundy, Tetrahedron Lett.1957 (1975).

The compounds of Formula A-2 and A-3 are utilized to prepare novelcompounds of Formula IV wherein D is --C═C(˜R₃)-- and R₃ is hydrogen asrepresented in Chart B. The compounds of Formulas A-2 and A-3 aresubjected to a Wittig reaction using an appropriate triphenylphosphoraneof Formula B-1 by procedures known in the art, then if desired thehydroxyl protecting groups which are present at at C-11 and C-15 areremoved by hydrolysis as generally described hereinabove to givecompounds of Formula B-2. The compounds of Formula B-2 are used toprepare the Formula B-3 compounds wherein Q' is the same as Q except itis other than --COOH. The acids of Formula B-2 can be esterified orconverted to an amide derivative by conventional means. The Formula B-2acids or an ester thereof can be reduced to the corresponding alcohol,i.e., Formula B-3 wherein Q' is --CH₂ OH by standard procedures, e.g.,by refluxing with lithium aluminum hydride in an ester solvent. Thealcohol thus obtained or a carboxylic acid ester derivative formula B-2can be oxidized to the corresponding carboxaldehyde which upon treatmentwith salt of hydroxylamine gives the oxime which is dehydrated to givethe nitrile, i.e., the compounds of Formula B-3 wherein Q' is CN. Theseconversions are all carried out by procedures generally known in theart. See, for example, the aforementioned British specifications whichdescribe the synthesis of various carbacyclin compounds, and inparticular G.B. 2,013,661. The amide thus obtained can be reduced to thecorresponding amines, i.e., compounds of Formula B-3 wherein Q' is --CH₂L₃ L₄ by using, e.g., lithium aluminum hydride. See U.S. Pat. No.4,073,808. Of course during the conversion of the Formula B-2 acids tothe various other C-1 position derivatives as represented by FormulaB-3, the C-11 and C-15 hydroxyl groups are protected as described hereinwhich groups can ultimately be deprotected by hydrolysis. The 5(E) and5(Z) isomers can be separated using either the compound of Formula B-2or Formula B-3.

The compounds of Formula IV wherein D is --CH═C(˜R₃) wherein R₃ ishydrogen and wherein Z is --(Ph)--(CH₂)_(q) -- are prepared as followsreference being made to Chart F. The ketones of Formulas A-2 and A-3 arereduced by conventional means using, for example, a borohydride reducingagent such as sodium, potassium or lithium borohydride, to thecorresponding alcohol. The alcohol is converted to a sulfate derivative,typically a methanesulfonate or toluenesulfonate by treatment withmethanesulfonyl chloride or toluenesulfonyl chloride in the presence ofa tertiary amine such as triethylamine. The sulfonate derivative istreated with sodium, lithium or potassium thiophenoxide to give thecompounds of Formula F-1. The thiophenoxide is preferably prepared byreacting equal molar amounts of thiophenol and a base such as potassiumtertiary butoxide just prior to reaction with the sulfonate. Thecompounds of Formula F-1 are oxidized to the correspondingphenylsulfonate using, e.g., m-chloroperbenzoic acid then treated with astrong base such as n-butyllithium to generate the corresponding anion.The anion is treated with an aldehyde of Formula F-2 and the resultingadduct is treated with acetic anhydride to give compounds of FormulaF-3. The compounds of Formula F-3 are treated with sodium amalgam byprocedures analogous to those described by P. J. Kocienski, et al.,"Scope and Stereochemistry of an Olefin Synthesis fromβ-Hydroxylsulphones", JCS Perkin I, 829-834 (1978) to give the olefinsof Formula F-4. The compounds of Formula F-4 are used to prepare theproducts of Formula F-5. The various hydroxyl groups are protected insuch a manner to permit selected hydrolysis to give ultimately thedeprotected products of Formula F-5. The R₂₁ silyl protecting group isconveniently removed via fluoride mediated hydrolysis using, e.g.,tetrabutyl ammonium fluoride to give the C-1 position alcohol of FormulaF-5 which is oxidized, using, e.g., Jones reagent, to the correspondingcarboxylic acid which in turn can be converted to the correspondingesters and amides. Also, the amides can be reduced to the amines ofFormula F-5, i.e., compounds wherein Q is --CH₂ L₃ L₄, and the alcoholor the carboxylic acid esters can be oxidized to the carboxaldehyde thenconverted to the nitrile via the oxime. The general procedures are thesame as those described hereinabove in connection with the preparationof compounds of Formula B-3. The 5(E) and 5(Z) isomers can be separatedconveniently using the alcohol corresponding to Formula F-4 and the C-11and C-15 hydroxyl protecting groups which may be present are removed bymild acid hydrolysis using, e.g., mixtures of water, tetrahydrofuran andacetic acid.

The compounds of Formula F-2 are prepared using known bis-acids of theformula ##STR8## wherein g is zero, one, 2 or 3, which are reduced tothe corresponding diol by conventional procedures, e.g., by usinglithium aluminum hydride. About equal molar amounts of the diol and asilylating reagent of R₂₁ are combined thereby preferentially silylatingthe alkanol hydroxyl although some di-silylated compound is produced.The mono-silylated compounds of the formula ##STR9## are oxidized to thealdehydes of Formula F-2 by conventional means, e.g., using manganesedioxide. See. U.S. Pat. No. 4,306,075.

The compounds of Formula IV wherein D is --CH═C(˜R₃) and R₃ is fluoroare prepared by reacting compounds of Formula A-2 and A-3 from Chart Ahereof with a sulfoxime of the formula G-1 as depicted in Chart G by thegeneral procedures described in U.S. Pat. No. 3,238,414 column 30, lines36 to 62. The compounds of Formula G-2 are then selectively hydrolyzedto the primary alcohol using, e.g., tetra-n-butylammonium fluoride. Thealcohols thus obtained can be oxidized to the corresponding C-1 positioncarboxylic acids, esters, amides, amines and nitriles of Formula G-3 bythe same general procedures described hereinabove in reference to thepreparation of compounds of Formula F-5 in Chart F. The 5(E) and 5(Z)isomers can be separated conveniently using the primary alcoholcorresponding to Formula G-2, and the C-11 and C-15 hydroxyl protectinggroups are removed by mild acid hydrolysis.

The sulfoxime of Formula G-1 are prepared by treating a compound of theformula ##STR10## wherein Z₁ R₂₁ have the meanings defined hereinabove,which compounds are known in the art (See U.S. Pat. No. 4,238,414) orare prepared by procedures generally known in the art with a strong basesuch as n-butyllithium in hexane to generate the anion which is treatedwith a fluorine source a preferred fluorine source being perchlorylfluoride, i.e., FClO₃.

The compounds of Formula IV can also be prepared utilizing compounds ofthe following Formula PX. In Formula PX, L₅₀ has the same meaning as Lonly R₁₂ is other than hydrogen; and R₁₃ is a protecting group asdefined hereinabove. ##STR11##

In referring to Chart A when the Compounds of Formula PX are substitutedfor and reacted in the manner analogous to that described for compoundsof Formula A-1 one obtains compounds of the following Formula PX(a)wherein R and R₃₀ have the meanings defined in Formula IV, and R₁₃ andL₅₀ have the meanings defined in Formula PX. ##STR12##

When the compounds of Formulas PX(a) are substituted for and treated ina manner analogous to that described for the compounds of Formulas A-2and A-3 as set forth in Chart B compounds of the following Formula PX(f)are obtained: ##STR13## wherein R₁₃, Z₁ and L₅₀ have the meaningsdefined hereinbefore and R and R₃₀ have the meanings defined in FormulaIV. The compounds of Formula PX(f) can be converted to compounds ofFormula PX(g) when treated in manners analogous to those described forthe compounds of Formula B-2 in Chart B. ##STR14##

In Formula PX(g) the various substituent groups R, R₃₀, L₅₀, R₁₃ and Z₁have the meanings defined in Formula PX(f) and Q₂ is the same as Q onlyQ₂ is not --COOH.

When the compounds of Formulas PX(a) are substituted for the compoundsof Formulas A-2 and A-3 in Chart F and the general procedures describedwith respect to Chart F are followed, or when the compounds of FormulasPX(a) are substituted for the compounds of Formulas A-2 and A-3 in ChartG and the general procedures described in Chart G are followedintermediates of the following respective Formulas PX(l) and PX(m) areobtained wherein g, Q, R₁₃, L₅₀, R and R₃₀ have the meanings definedhereinbefore ##STR15##

The intermediates of Formulas PX(f), PX(g), PX(l) and PX(m) are utilizedin preparing the CBA₂ compounds of Formula A-1 (Chart A). Initially theintermediates of Formulas PX(f), (g), (l) and (m) are hydrolyzed toremove the R₁₃ protecting group thus giving the primary alcoholderivatives which are oxidized tothe corresponding aldehyde byconventional procedures, e.g., under the conditions of a Collinsreaction. To prepare compounds of Formula A-1 one utilizes aldehydes ofthe following general Formula MX which are obtained by oxidation of thecorresponding C-12 position substituted alcohol by conventionalprocedures. The alcohols are known in the art or are readily prepared byprocedures known in the art. ##STR16## In the above Formula MX, L₅₀ hasthe meaning defined in Formula PX above.

The "C-12 aldehydes" corresponding to the intermediates of FormulasPX(f), PX(g), PX(l) and PX(m) and the aldehydes of Formula MX are thentreated as described hereinbelow, wherein for purposes of convenienceonly the chemical transformations which occur at the "C-12 position" ofsaid compounds are depicted.

The "C-12" aldehydes are subject to a Wittig reaction with an alkylphosphonate derivative of the formula ##STR17## which is obtained byaddition of the anion of dialkylmethylphosphonate, i.e., ##STR18## withan ester of the formula ##STR19## by procedures known in the art. R'₁₇and Lx have the same meanings as R₁₇ and L₁ except ##STR20## is otherthan --C_(p) H_(2p) CH═CH₂. There results compounds wherein the "C-12position" is substituted with ##STR21## the ketone of which is reducedto the various M groups defined hereinabove to give the correspondingcompounds wherein the "C-12 position" is substituted with ##STR22##These trans-vinyl derivatives can be hydrogenated to give thecorresponding compounds wherein the "C-12 position" is substituted with##STR23## or can be halogenated followed by tetradehydrohalogenation togive the corresponding compounds wherein the "C-12 position" issubstituted with ##STR24## and upon hydrogenation with a Lindlarcatalyst gives the cis-vinyl derivatives, i.e., compounds wherein the"C-12 position" is substituted with ##STR25## Compounds corresponding tothose of Formulas MX or PX(f), (g), (l) and (m) wherein the "C-12position" is substituted with ##STR26## can also be prepared by treatingthe appropriate "C-12" aldehyde compound with an alkylphosphonatedepicted above only wherein ##STR27## is --C_(p) H_(2p) CH═CH₂ or##STR28## to give the corresponding compounds wherein the "C-12position" is substituted with ##STR29## the trans-vinyl group of whichis reduced, e.g., by dissolving metal reduction followed by reduction ofthe ketone to the various M groups defined hereinabove.

Additionally, treatment of the "C-12" aldehydes with a phosphine of theformula (alkyl)₃ P═CHCHO under the conditions of a Wittig reaction givesthe corresponding compounds wherein the "C-12" position is substitutedwith trans--CH═CHCHO which can be reduced to give the correspondingcompound wherein the "C-12 position" is substituted with --CH₂ CH₂ CHO.Also the compounds corresponding to the Formula MX or Formulas PX(f),(g), (l) or (m) only wherein the "C-12 position" is substituted withtrans--CH═CHCHO can be reduced to the corresponding alcohol, i.e.,trans--CH═CHCH₂ OH then hydrogenated to give compounds wherein the "C-12position" is substituted with --CH₂ CH₂ CH₂ OH. Or, the trans-vinylalcohol can be halogenated then tetradehydrohalogenated to give thecorresponding ethinyl, i.e., compounds wherein the "C-12 position" issubstituted with --C.tbd.CCH₂ OH, which upon hydrogenation with aLindlar catalyst gives the cis-vinyl alcohol compounds. The thusobtained alcohols, i.e., the compounds corresponding to those ofFormulas MX or PX(f), PX(g), PX(l) and PX(m) only wherein the "C-12position" is substituted with trans--CH═CHCH₂ OH, --CH₂ CH₂ CH₂ OH,--C.tbd.CCH₂ OH or cis--CH═CHCH₂ OH can then be oxidized to the aldehydeto give the corresponding compounds wherein the terminal primary alcoholcontained in the "C-12" substituent is --CHO. The aldehydes are thentreated with a Grignard reagent of the formula haloMgC_(p) H_(2p) CH═CH₂or an alkyllithium of the formula LiC_(p) H_(2p) CH═CH₂, or an acetylideanion of the formula --C.tbd.CC_(p) H_(2p) CH₃ or an alkylphosphonatedepicted hereinabove to give compounds corresponding to those ofFormulas MX or PX(f), (l), (m) and (g) only wherein the "C-12 position"is substituted with ##STR30## wherein Y, L₁ and R₁₇ have the meaningsdefined hereinabove. These thus obtained alcohol derivatives can beoxidized to the ketone and treated with methyl lithium or a methylGrignard to give the corresponding compounds wherein the "C-12 position"is substituted with ##STR31## wherein R₁₄ is methyl.

Upon completion of the above-described "C-12 position" transformationswith respect to the compounds of Formula MX the resulting lactonederivatives are converted to the compounds of Formula A-1 via lactol anddiketone phosphonate derivatives in a manner analogous to that describedin U.S. Pat. No. 4,306,075 in reference to Chart A thereof.

The CBA₁ compounds of Formula IV, i.e., compounds of Formula IV whereinD is --CH₂ CH₂ -- are prepared by reducing the compounds of FormulasPX(f), PX(g) and PX(l) to the corresponding derivatives wherein thecarbon atoms at positions C-5 and C-6 are saturated. This reduction iscarried out by procedures generally known in the art, such as thegeneral methods described in British Published application 2,017,699.For example, the reduction may be achieved by a standard hydrogenationin the presence of a catalyst such as palladium on charcoal or platinumdioxide in a lower alcohol such as ethanol or methanol. The resulting5,6-dihydro intermediates are then utilized to prepare the CBA₁compounds of Formula IV by the same general procedures describedhereinabove in connection with the conversion of compounds of FormulasPX(f), PX(g) and PX(l) to CBA₂ compounds of Formula IV.

A preferred method of preparing the CBA₁ compounds of Formula IV whereinZ is trans--CH₂ CH═CH-- is to utilize the appropriate intermediates ofFormulas PX(m) and PX(g) wherein Z₁ is --CH₂ --(CH₂)_(f) --C(R₄)₂ --wherein f is one and R₄ is hydrogen and wherein Q is a carboxylic acidester, preferably the methyl ester which derivatives are referred toherein as the butanoic acid esters. The butanoic acid ester derivativesare treated with a lithium amide base and phenylselenyl chloride to givethe corresponds α-phenylselenyl derivatives which are reduced by, e.g.,general procedures described in U.K. application GB2,017,699 to give the5,6-dihydro intermediates. The 5,6-dihydro intermediates aredehydrophenylselenized by treatment with hydrogen peroxide to giveintermediates corresponding to Formulas PX(g) to PX(k) wherein Z₁ is--CH₂ CH═CH₂, Q² is a carboxylic acid ester and the carbon atoms atpositions 5 and 6 are saturated, which intermediates can be converted tothe corresponding derivatives wherein the terminal C-1 positioncorresponds to Q as defined herein by the general procedures describedhereinabove in connection with the preparation of compounds of FormulaB-3 in Chart B. These 5,6-dihydro intermediates are then converted tothe CBA₁ compounds of Formula IV wherein Z is --CH₂ CH═CH-- by treatmentin a manner analogous to that described hereinabove in connection withthe conversion of Formulas PX(f)-PX(r) to CBA₂ compounds of Formula IV.

When the alkyl ester has been obtained and an acid is desired,saponification procedures, as known in the art for PGF-type compoundsare employed.

When an acid has been prepared and an alkyl, cycloalkyl, or aralkylester is desired, esterification is advantageously accomplished byinteraction of the acid with appropriate diazohydrocarbon. For example,when diazomethane is used, the methyl ester is produced. Similar use ofdiazoethane, diazobutane, and 1-diazo-2-ethylhexane, and diazodecane,for example, gives the ethyl, butyl, and 2-ethylhexyl and decyl esters,respectively. Similary, diazocyclohexane and phenyldiazomethane yieldcyclohexyl and benzyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing asolution of the diazohydrocarbon in a suitable inert solvent, preferablydiethyl ether, with the acd reactant, advantageously in the same or adifferent inert diluent. After the esterification reaction is completethe solvent is removed by evaporation, and the ester purified if desiredby conventional methods, preferably by chromatography. It is preferredthat contact of the acid reactants with the diazohydrocarbon be nolonger than necessary to effect the desired esterification, preferablyabout one to about 10 minutes, to avoid undesired molecular changes.Diazohydrocarbons are known in the art or can be prepared by methodsknown in the art. See, for example, Organic Reactions, John Wiley andSons, Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).

An alternative method for alkyl, cycloalkyl or aralkyl esterification ofthe carboxy moiety of the acid compounds comprises transformation of thefree acid to the corresponding substituted ammonium salt, followed byinteraction of that salt with an alkyl iodide. Examples of suitableiodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide,tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyliodide, phenethyl iodide, and the like.

Various methods are available for preparing phenyl or substituted phenylesters within the scope of the invention from corresponding aromaticalcohols and the free acid, differing as to yield and purity of product.

With regard to the preparation of the phenyl, particularly p-substitutedphenyl esters disclosed herein (i.e., Q is --COOR₅ and R₅ isp-substituted phenyl), such compounds are prepared by the methoddescribed in U.S. Pat. No. 3,890,372. Accordingly, by the preferredmethod described therein, the p-substituted phenyl ester is preparedfirst by forming a mixed anhydride, particularly following theprocedures described below for preparing such anhydrides as the firststep in the preparation of amido and cycloamido derivatives.

This anhydride is then reacted with a solution of the phenolcorresponding to the p-substituted phenyl ester to be prepared. Thisreaction proceeds preferably in the presence of a tertiary amine, suchas pyridine. When the conversion is complete, the p-substituted phenylester has been recovered by conventional techniques.

A preferred method for substituted phenyl esters is that disclosed inU.S. Pat. No. 3,890,372 in which a mixed anhydride is reacted with anappropriate phenol or naphthol. The anhydride is formed from the acidwith isobutylchloroformate in the presence of a tertiary amine.

Phenacyl-type esters are prepared from the acid using a phenacylbromide, for example p-phenylphenacyl bromide, in the presence of atertiary amine. See, for example, U.S. Pat. No. 3,984,454, GermanOffenlegungsschrift 2,535,693, and Derwent Farmdoc No. 16828X.

The phthalidyl esters are obtained by treating the corresponding acidwith a phthalidyl halide such as the bromide in, e.g.,dimethyl-formamide in the presence of an amine base. The phosphoranylesters are obtained by treating the corresponding acid with a 1-haloderivative, e.g., the 1-chloro derivative of3-(5,5-di(hydroxymethyl)-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-ylP-oxide and3-(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-yl P-oxidein, e.g., acetonitrile in the presence of an organic amine.

Carboxyamides (Q is --COL₂) are prepared by one of several amidationmethods known in the prior art. See, for example, U.S. Pat. No.3,981,868, issued Sept. 21, 1976, for a description of the preparationof the present amido and cycloamido derivatives of prostaglandin-typefree acids and U.S. Pat. No. 3,954,741 describing the preparation ofcarbonylamido and sulfonylamido derivatives of prostaglandin-type freeacids.

The prepared method by which the present amido and cycloamidoderivatives of the acids are prepared is, first, by transformation ofsuch free acids to corresponding mixed acid anhydrides. By thisprocedure, the carbacyclin-type free acid is first neutralized with anequivalent of an amine base, and thereafter reacted with a slightstoichiometric excess of a chloroformate corresponding to the mixedanhydride to be prepared.

The amine base preferred for neutralization is triethylamine, althoughother amines (e.g., pyridine, methyldiethylamine) are likewise employed.Further, a convenient, readily available chloroformate for use in themixed anhydride production is isobutyl chloroformate.

The mixed anhydride formation proceeds by conventional methods andaccordingly the free acid is mixed with both the tertiary amine base andthe chloroformate in a suitable solvent (e.g., aqueous tetrahydrofuran),allowing the reaction to proceed at -10° C. to 20° C.

Thereafter, the mixed anhydride is converted to the corresponding amidoor cycloamido derivatives by reaction with the amine corresponding tothe amide to be prepared. In the case where the simple amide (--NH₂) isto be prepared, the transformation proceeds by the addition of ammonia.Accordingly, the corresponding amine (or ammonia) is mixed with themixed anhydride at or about -10° to +10° C., until the reaction is shownto be complete.

Thereafter, the novel amido or cycloamido derivative is recovered fromthe reaction mixture by conventional techniques.

The carbonylamido and sulfonylamido derivative of the presentlydisclosed carbacyclin compounds are likewise prepared by known methods.See, for example, U.S. Pat. No. 3,954,741 for description of the methodsby which such derivatives are prepared. By this known method the acid isreacted with a carboxyacyl or sulfonyl isocyanate, corresponding to thecarbonylamido or sulfonylamido derivative to be prepared.

By another, more preferred method the sulfonylamido derivatives of thepresent compounds are prepared by first generating the PG-type mixedanhydride, employing the method described above for the preparation ofthe amido and cycloamido derivatives. Thereafter, the sodium salt of thecorresponding sulfonamide is reacted with the mixed anhydride andhexamethylphosphoramide. The pure carbacyclin sulfonylamido derivativeis then obtained from the resulting reaction mixture by conventionaltechniques.

The sodium salt of the sulfonamide corresponding to the sulfonylamidoderivative to be prepared is generated by reacting the sulfonamide withalcoholic sodium methoxide. Thus, by a preferred method methanolicsodium methoxide is reacted with an equal molar amount of thesulfonamide. The sulfonamide salt is then reacted, as described above,with the mixed anhydride, using about four equivalents of the sodiumsalt per equivalent of anhydride. Reaction temperatures at or about 0°C. are employed.

The compounds of this invention prepared by the processes of thisinvention, in free acid form, are transformed to pharmacologicallyacceptable salts by neutralization with appropriate amounts of thecorresponding inorganic or organic base, examples of which correspond tothe cations and amines listed hereinabove. These transformations arecarried out by a variety of procedures known in the art to be generallyuseful for the preparation if inorganic, i.e., metal or ammonium salts.The choice of procedure depends in part upon the solubilitycharacteristics of the particular salt to be prepared. In the case ofthe inorganic salts, it is usually suitable to dissolve an acid of thisinvention in water containing the stoichiometric amount of a hydroxide,carbonate, or bicarbonate corresponding to the inorganic salt desired.For example, such use of sodium hydroxide, sodium carbonate, or sodiumbicarbonate gives a solution of the sodium salt. Evaporation of thewater or addition of a water-miscible solvent of moderate polarity, forexample, a lower alkanol or a lower alkanone, gives the solid inorganicsalt if that form is desired.

To produce an amine salt, an acid of this invention is dissolved in asuitable solvent of either moderate or low polarity. Examples of theformer are ethanol, acetone, and ethyl acetate. Examples of the formerare ethanol, acetone, and ethyl acetate. Examples of the latter arediethyl ether and benzene. At least a stoichiometric amount of the aminecorresponding to the desired cation is then added to that solution. Ifthe resulting salt does not precipitate, it is usually obtained in solidform by evaporation. If the amine is relatively volatile, any excess caneasily be removed by evaporation. It is preferred to use stoichiometricamounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingan acid of this invention with the stoichiometric amount of thecorresponding quaternary ammonium hydroxide in water solution, followedby evaporation of the water.

EXAMPLE 1 (a)6β-(Benzyloxymethyl)-7α-(tetrahydropyran-2-yloxy)-1β-(methyl)-bicyclo[3.3.0]octan-3-one

To a mixture of 3.46 g of copper iodide in 180 ml of diethyl ether,cooled to -10° C. in a carbon tetrachloride-dry ice bath, is addeddropwise 28.0 ml (36.42 mmoles) of methyl lithium over a 5 minute periodand stirring is continued for 20 minutes at -20° to -23° C., after which6β-(benzyloxy)methyl]-7α-(tetrahydropyran-2-yloxy)bicyclo[3.3.0]octen-3-onein 98 ml of diethyl ether is added dropwise over about one hour.Stirring is continued at -20° C. for about 2 hours then under a nitrogenatmosphere the mixture is combined with 100 ml of 0.5M ammoniumchloride, cooled with stirring. The organic layer is separated, and theaqueous layer is extracted with 500 ml of ether, dried and the combinedorganic extracts are concentrated on a rotary evaporator to give 2.3 gof crude material which is chromatographed with silica gel using ethylacetate-Skelly "B" for packing and eluting to give the purified titleproduct as a colorless oil.

TLC: Ethyl acetate-Skelly "B" (1:2 (R_(f) 0.48.

(b)12β-(Benzyloxymethyl)-9β-methyl-13,14,15,16,17,18,19,20-octanor-6a-carba-prostaglandinI₂, 11-tetrahydropyranyl ether

Sodium hydride (6.93 g, 60% oil dispersion, 173.1 mmol, 11.5 eq) isstirred in 7 ml of dry hexane, allowed to settle and the supernatantcarefully drawn off with pipette. After repeating above procedure using10 ml of hexane, 132 ml of dimethylsulfoxide is added and the mixtureheated in oil bath at 75° C. under nitrogen for 1.3 hours. Thedimethylsulfoxide anion is cooled to about 10° C., treated portionwisewith solid 4-carboxybutyl triphenylphosphonium bromide (38.03 g, 85.8mmol, 5.7 eq) over a short period of time (1 to 2 minutes). The contentsare stirred at ambient temperature for 1.2 hours additionally, thentreated dropwise over a 5 minute period with the product of 1(a) above(5.39 g, 15.06 mmol) in 46 ml of dimethylsulfoxide at room temperature.The reaction mixture is kept in oil bath at 45° C. for about 43 hours,cooled in ice bath, poured into 350 ml of 2N potassium bisulfatesolution containing 150 ml of ice and extracted with ether three times.The combined ether extracts are dried over anhydrous sodium sulfate andconcentrated at reduced pressure to yield 17.8 g of crude material.Following chromatography with 500 g of silica gel packed and eluted withacetone-Skelly "B" (1:4) plus 0.25% acetic acid, 5.46 g (82%) of thetitle product is isolated as a 5E and 5Z mixture.

TLC: Acetone-Skelly "B"-acetic acid (20:80:.25) R_(f) 0.21.

(c)12β-Hydroxymethyl-9β-methyl-13,14,15,16,17,18,19,-20-octanor-6a-carbaprostaglandin I₂, 11-tetrahydropyranyl ether

Liquid ammonia (100 ml) is distilled into a solution of the product of1(b) above (5.46 g, 12.34 mmol) in 100 ml of tetrahydrofuran and 2.0 mlof t-butyl-alcohol at -50° C. utilizing a dry ice-acetone trap. Thetemperature is maintained at about -40° C. while freshly scraped lithiumwire (4") is added in small pieces portionwise. After 15 minutes anadditional 2" of lithium wire is added causing the gray suspension tochange to blue. After an additional 30 minutes solid NH₄ Cl is added toquench excess lithium and a strong nitrogen stream is swept throughflask to expel the excess ammonia. To the solid residue is added 100 mlof saturated ammonium chloride solution plus 100 ml of 2W potassiumbisulfate solution. The contents are extracted with ethyl acetate twotimes, the combined ethyl acetate extracts washed with saturated brine(1×75 ml) and dried over anhydrous sodium sulfate. Concentration invacuo leads to 4.54 q of colorless oil. Separation of the 5Z (42%) and5E (39%) isomers of the title compound is achieved by HPLC (2-`C` and3-`B` prepacked Merck columns in series) using ethyl acetate-Skelly "B"91:2) containing 0.25% acetic acid.

TLC: Ethyl acetate-Skelly "B" (1:1) with 0.25% acetic acid R_(f) 5Z0.26, R_(f) 5E 0.20.

(d)(5E)-12β-Hydroxymethyl-9β-methyl-13,14,15,16,17,18,19,20-octanor-6a-carba-prostaglandinI₂ methyl ester, 11-tetrahydropyranyl ether

To a stirred solution of the 5E isomer of 1(c) above (1.72 g, 4.87 mmol)in 25 ml of acetonitrite at room temperature is addeddiisopropylethylamine (1.88 g, 14.61 mmol, 3 eq) at once followed bymethyl iodide (3.46 g, 24.36 mmol, 5 eq) in like manner. After 21 hoursat room temperature the reaction mixture is diluted with a sufficientamount of ether, washed successively with saturated brine (1×50 ml), 10%sodium thiosulfite (1×20 ml), and saturated brine (1×25 ml). Thecombined aqueous washings are extracted with ether (1×100 ml) and thecombined organic extracts dried over anhydrous sodium sulfate.Concentration in vacuo provides 1.68 g (94%) of the title product as adark brown oil.

TLC: Ethyl acetate-Skelly "B" (1:1) with 1% acetic-acid R_(f) 0.44.

(e)(5E)-12β-Formyl-9β-methyl-13,14,15,16,17,18,19,20-octanor-6a-carba-prostaglandinI₂ methyl ester, 11-tetrahydropyranyl ether

To a suspension of dry chromium trioxide (0.793 g, 7.93 mmol, 6 eq) in13 ml of methylene chloride at room temperature is added pyridine (1.25g, 15.84 mmol, 12 eq) dropwise followed by 1 ml methylene chloriderinse. After 1.3 hours of stirring at ambient temperature the reactionmixture is cooled in an ice bath while the product of 1(d) above (0.485g, 1.32 mmol) in 6 ml of methylene chloride is added dropwise over a 5minute period. The cooling bath is removed, 5 ml of additional methylenechloride is added and the contents are stirred for 45 minutes at ambienttemperature. Subsequently, the mixture is diluted with ether, celite andstirred at room temperature for about 30 minutes. The contents arefiltered through a pad of celite and the filtrate concentrated atreduced pressure to obtain 475 mg of crude product as a brown oil.Purification, effected with a 50 g silica gel column packed and elutedwith ethyl acetate-Skelly "B" (1:4), gives 370 mg (76%) of pure titlecompound.

TLC: Ethyl acetate-Skelly "B" (1:4) R_(f) 0.32.

EXAMPLE 2 (a) 1-Bromo-2-butyne

To a stirred solution of 2-butyne-1-ol (10.0 g, 0.143 mol) in 30 ml ofether at 0° C. is added pyridine (4.84 g, 0.06 mol, 0.43 eq) at oncefollowed by careful dropwise addition of phosphorous tribromide (26.3 g,0.097 mol, 0.68 eq) over a 30 minute period. An additional 10 ml ofether was added to facilitate stirring and the contents warmed to refluxfor 2 hours. The reaction mixture is cooled in ice bath, treatedcautiously with 70 ml of ice water and extracted with ether (2×150 ml).The combined ether extracts are washed with saturated brine (2×25 ml),the combined aqueous washings extracted with ether (1×50 ml) and thecombined organic extracts dried over anhydrous sodium sulfate. Thefiltrate is concentrated on a rotary evaporator while keeping the waterbath temperature less than 10° C. Twice the contents are diluted with100 ml of pentane and reconcentrated as before. The heterogenous lookingoil is dissolved in 300 ml of pentane, dried over anhydrous magnesiumsulfate and reconcentrated as before to obtain 11.0 g (58%) of1-bromo-2-butyne.

(b) 2-Methyl-4-hexynoic acid

Diisopropylamine (26.0 g, 0.257 mmol, 3.1 eq) in 130 ml oftetrahydrofuran initially at -50° C. is treated dropwise withn-butyllithium (98.8 ml, 1.6 M, 0.158 mol, 1.9 eq) over an 8 minuteperiod while allowing the temperature to rise to -25° C. After 5 minuteslonger at -20° C., the reaction mixture is treated dropwise with amixture of hexamethylphosphoramide (17.8 g, 0.099 mol, 1,2 eq) andpropionic acid (6.14 g, 0.083 mol, 1.0 eq) over a 7 minute period whilethe temperature rises to 0° C. Following addition the reaction mixtureis warmed to room temperature and maintained there for 35 minutes. Thecontents are then cooled to 0° C. in an ice bath, treated dropwise overa 12 minute period with 1-bromo-2-butyne (11.0 g, 0.083 mol, 1.0 eq) in8 ml of tetrahydrofuran. The temperature, which rises to 16° C. duringaddition, is allowed to warm to room temperature thereafter where it ismaintained for 2 hours. The contents are carefully poured into 300 ml of10% HCl with stirring (exothermic) followed by 500 ml of ether-pentane(1:1). The organic layer is separated and the aqueous phase extracted 2more times with etherpentane (1:1) giving 1800 ml of total extractvolume. The combined extracts are washed with water 2×60 ml) and thecombined organic extracts are dried over anhydrous sodium sulfate,magnesium sulfate and concentrated at reduced pressure to provide 11.1 g(over theory) of 2-methyl-4-hexynoic acid which is converted to themethyl ester by treatment with methyl iodide.

(c) 3-Methyl-2-oxo-hept-5-yne phosphonic acid dimethyl ester

A solution of dimethyl methylphosphonate (22.47 g, 181.24 mmol) in 260ml of tetrahydrofuran is cooled to -78° C. and treated dropwise withn-butyllithium (113 ml, 181.24 mmol), 1.6 M in hexane) over a 25-minuteperiod. The mixture is stirred an additional 30 minutes at -78° C., thentreated dropwise with 2-methyl-4-hexynoic acid methyl ester (7.25 g,51.78 mmols) in 65 ml of tetrahydrofuran over a period of 10 minutes.The contents are stirred for another 3 hours at -78° C. and then 17hours at ambient temperature. The reaction mixture is cooled to 8° C.,treated with 14 ml of acetic acid, stirred at ambient temperature for 30minutes, then concentrated in vacuo. The residue is treated with 100 mlof saturated brine and 100 ml of ice water to form a slurry andextracted 3 times with ether (1400 ml total) and once with 250 ml ofethyl acetate-ether (1:1). The combined organic extracts are washed withsaturated brine (2×75 ml), the combined aqueous washings extracted withethyl acetate-ether (1:1, 1×100 ml) and dried over anhydrous sodiumsulfate, and concentrated at reduced pressure. Vacuum distillation gives10.21 g of the title product, m.p. 121°-125° C., 0.15 mmHg.

EXAMPLE 3 (a)(5E)-9β-Methyl-15-keto-16(R,S)-16-methyl-18,19-tetradehydro-6a-carba-prostaglandinI₂, methyl ester, 11-tetrahydropyranyl ether

Thallium ethoxide (0.634 g, 2.55 mmol, 1.3 eq) in 10 ml of benzene at 6°C. is treated with 3-methyl-2-oxohept-5-yne phosphonic acid dimethylester (0.613 g, 2.64 mmol, 1.35 eq) in 2.5 ml of benzene. After stirringfor 50 minutes at 6° to 10° C.,(5E)-12β-formyl-9β-methyl-13,14,15,16,17,18,19,20-octanor-6a-carba-prostglandinI₂ methyl ester, 11-tetrahydropyranyl ether (0.715 g, 1.96 mmol) in 5 mlof benzene is added at once to mixture at 6° C. After stirring one hourlonger at ambient temperature, the reaction mixture is again cooled to6° C., quenched with 0.5 ml of acetic acid followed by addition ofaqueous potassium iodide to precipitate the thallium as a yellow salt.The contents are diluted with ether, stirred at room temperature andfiltered through a pad of celite. The organic layer is washedsuccessively with ice water (1×50 ml), saturated sodium bicarbonate(1×75 ml), saturated brine (1×50 ml) and all aqueous washings extractedwith ether (1×75 ml). The combined organic extracts are dried overanhydrous sodium sulfate and concentrated in vacuo to obtain 1.25 g ofcrude product as a yellow oil. Chromatography with 100 g of silica gelusing ethyl acetate-Skelly "B" (1:8) for packing and (1:6) for eluting,gives 744 mg (81%) of the title compound.

TLC: Ethyl acetate-Skelly "B" (1:9) R_(f) 0.11.

(b)(5E)-9β-Methyl-15(R,S)-16-methyl-18,19-tetradehydro-6a-carba-prostaglandinI₂, methyl ester, 11-tetrahydropyranyl ether

To a solution of 0.24 g (0.510 mmole) of(5E)-9β-methyl-15-keto-16(R,S)-16-methyl-18,19-tetradehydro-6a-5Z-carba-prostaglandinI₂, methyl ester, 11-tetrahydropyranyl ether in 6 ml of methanol, cooledto -25° C., is added 0.027 g (0.71 mmole) of sodium borohydride in about1 ml of methanol and the mixture is stirred at -25° to -20° C. then at-20° to -15° C. for about 30 minutes after which an additional 0.027 g(0.71 mmole) then another 0.015 g (0.39 mmole) of sodium borohydride isadded with continued stirring. After about 20 minutes the mixture istreated with 7 ml of 2N potassium bisulfate solution and ice water thenextracted with ethyl acetate. The organic extract is washed (2×20 ml)with saturated brine, and the aqueous washings are extracted with ethylacetate. The combined organic extracts are dried over anhydrous sodiumsulfate, concentrated in vacuo, and the residue chromatographed onsilica gel eluting with ethyl acetate-Skelly "B" to give the titleproduct as a colorless oil.

TLC: Ethyl acetate-Skelly "B" (1:4) R_(f) 0.15, R_(f) 0.11.

(c) (5E)-9β-Methyl-15(R) and15(S)-16(R,S)-16-methyl-18,19-tetradehydro-6a-carba-prostaglandin I₂,methyl esters

Acid hydrolysis of the product of 3(b) above (0.823 g, 1.74 mmol) isaccomplished by stirring with 16.5 ml of aceticacid-water-tetrahydrofuran (20:10:3) at room temperature for 7 hours.The contents are cooled in ice bath, treated with solid sodiumbicarbonate plus ice and extracted with ethyl acetate two times (450 mltotal volume). The combined organic extracts are washed with 5% sodiumbicarbonate (1×25 ml), saturated brine (1×25 ml) and the aqueouswashings extracted with ethyl acetate (1×50 ml). The combined organicextracts are dried over anhydrous sodium sulfate and concentrated atreduced pressure to give 771 mg crude diol. LPLC chromatography using aprepacked Merck "B" column and ethyl acetate-Skelly "B"(1:2) 1 l; then(2:3) resolves the 15(R) and 15(S) isomers of the title product.

TLC: Ethyl acetate-Skelly "B" (1:1) R_(f), 15(R), 0.28; R_(f), 15(S),0.18. Acetone-methylene chloride (1:4) R_(f), 15(R), 0.39; R_(f), 15(S),0.18.

IR (neat, cm⁻¹): 15(R) and 15(S) identical; 3410 (s, broad), 2950 (s),1860 (w,sh), 1740 (s), 1715 (sh), 1450 (m), 1430 (m), 1370 (w), 1250(w), 1170 (w), 1070 (w), 1010 (w), 970 (m).

NMR (CDCl₃, δ): 15(R), 5.58 (m, 2H), 5.35-5.00 (m, 1H), 4.53-3.55 (m,2H), 3.65 (s, 3H), 2.80-1.20 (m, 22H), 1.05 (s, 3H), 1.00 (d, 3H, 7 Hz).15(S), 5.48 (m, 2H), 5.34-4.94 (m, 1H), 4.16-3.50 (m, 2H), 3.66 (s, 3H),3.23 (s, 2H), 2.50-1.15 (m, 20H), 1.06 (s, 3H), 0.96 (d, 3H, 7 Hz).

Mass Spectrum: Calculated for C₃₀ H₅₂ O₄ Si₂ : 532.3404. Found: 15(R),532.3396; 15(S), 532.3406.

(d) (5E)-9β-Methyl-15(R) and15(S)-16(R,S)-16-methyl-18,19-tetradehydro-6a-carba-prostaglandin I₂

Base hydrolysis of the 15(S) isomer of 3(c) above (0.324 g, 0.834 mmol)in 12 ml of methanol at room temperature is achieved by adding potassiumhydroxide (1.4 ml, 3N, 4.2 mmol, 5 eq) at once. After 7.5 hours thereaction mixture is cooled to 0° to 5° C. in ice bath, treated with 13ml of 2N potassium bisulfate plus 20 ml of saturated brine. The contentsare extracted with ethyl acetate 2 times, the combined organic extractswashed with saturated brine (1×25 ml), dried over anhydrous sodiumsulfate and concentrated in vacuo. Chromatography with 19 g of CC-4 acidwashed silica gel using ethyl acetate-Skelly "B" (1:2) for packing andeluting gives 261 mg (84%) of the title products.

The 15(S) compound is characterized as follows:

TLC: Ethyl acetate-Skelly "B" (1:1) with 1% acetic acid R_(f) 0.12.

IR (neat, cm⁻¹): 3330 (s, broad), 2900 (s), 2650 (broad shoulder), 1700(s), 1450 (m), 1370 (w), 1240 (w), 1130 (w), 1060 (w), 1000 (w), 970(m).

NMR (CDCl₃, δ): 5.95 (s, 3H), 5.43 (s, 2H), 5.26-4.84 (m, 2H), 4.20-3.45(m, 2H), 2.43-1.08 (m, 20H), 1.05 (s, 3H), 1.08-0.51 (m 3H).

Mass Spectrum: Calculated for C₃₂ H₅₈ O₄ Si₃ : 590.3643. Found:590.3633.

The 15(R) compound is similarly prepared and is characterized asfollows:

TLC: Ethyl acetate:Skelly "B" (1:1) with 1% acetic acid, R_(f) 0.24.

NMR (CDCl₃, δ): 5.60 (s, 6H), 5.33-4.94 (m, 1H), 4.27-3.60 (m, 2H),2.78-1.20 (m, 20H), 1.07 (s, 3H), 1.20-0.70 (m, 3H).

EXAMPLE 4

(a) When in the procedure of Example 1(d) the (5Z) isomer of12β-hydroxymethyl-9β-methyl-13,14,15,16,17,18,19,20-octanor-6a-carba-prostaglandinI₂, 11-tetrahydropyranyl ether is substituted for the (5E) isomer oneobtains(5Z)-12β-hydroxymethyl-9β-methyl-13,14,15,16,17,18,19,20-octanor-6A-carba-prostaglandinI₂ methyl ester, 11-tetrahydropyranyl ether which is converted to thecorresponding 12β formyl derivative by the procedure of Example 1(e).

(b) When in the procedure of Example 3(a)(5Z)-12β-formyl-9β-methyl-13,14,15,16,17,18,19,20-octanor-6a-carba-prostaglandinI₂ methyl ester, 11-tetrahydropyranyl ether is substituted for the (5E)isomer and the procedure of Example 3(a) through 3(c) is followed oneobtains (5Z)-9β-methyl-15(S)and15(R)-16(R,S)-16-methyl-18,19-tetradehydro-6a-carba-prostaglandin I₂,methyl esters (TLC: ethyl acetatecyclo hexane; 15(S) compound, R_(f)0.27; 15(R) compound, R_(f) 0.37) which are converted to thecorreponding C-1 carboxylic acids by the procedure of Example 3(d).(5Z)-9β-methyl-15(S)-16(R,S)-16-methyl-18,19-tetradehydro-6a-carba-prostaglandinI₂ is characterized as follows:

NMR (CDCl₃, δ): 6.6 (s, 3H); 5.5 (s, 2H); 5.2 (m, 1H); 4.1-3.6 (m,2H);1.8 (s, 3H); 1.05 (s, 3H); 0.95 (d, 3H).

IR (thin film): 3365 (OH), 2602 (COOH), 1709 (C═O), 1435, 1432, 1411,1374, 13331, 1296, 1244, 1205, 1175, 1152, 1119, 1098, 1073, 1044, 1008,971 cm⁻¹.

The corresponding 15(R)compound is characterized as follows:

NMR (CDCl₃, δ): 5.7 (m, 5H); 5.2 (m, 1H); 4.3-3.65 (m, 2H); 1.75 (s,3H); 1.05 (s, 3H); 0.95 (d, 3H).

IR (thin film): 3368 (OH), 2649 (COOH), 1710 (C═O), 1452, 1432, 1411,1375, 1349, 1335, 1310, 1293, 1247, 1203, 1172, 1151, 1117, 1102, 1072,1042, 1009, 972 cm⁻¹.

EXAMPLE 5

(a) When in the procedure of Example 1(b)6β-(benzyloxymethyl)-8a-(tetrahydropyran-2-yloxy)-tricyclo[4.3.1]nonan-4-one,which is prepared from6β-(benzyloxymethyl)-7a-(tetrahydropyran-2-yloxy)bicyclo[3.3.0]octen-3-onein a manner analogous to that described in Example 29 U.S. Pat. No.4,306,075, is substituted for6β-(benzyloxymethyl)-7β-(tetrahydropyran-2-yloxy)-1β-(methyl)bicyclo[3.3.0]octan-3-oneand the procedure of 1(b) and 1(c) is followed one obtains the (5E) and(5Z) isomers of12β-hydroxymethyl-6aβ,9β-methano-13,14,15,16,17,18,19,20-octanor-6a-carba-prostaglandinI₂, tetrahydropyranyl ether, and when the thus obtained (5Z) isomer issubstituted for(5E)-12β-hydroxymethyl-9β-methyl-13,14,15,16,17,18,19,20-octanor-6a-carba-prostaglandinI₂, 11-tetrahydropyranyl ether in Example 1(d) and the procedure ofExample 1(d) and 1(e) is followed one obtains(5Z)-12b-formyl-6aβ,9β-methano-13,14,15,16,17,18,19,20-octanor-6a-carba-prostaglandinI₂ methyl ester, 11 -tetrahydropyranyl ether.

(b) When in the procedure of Example 3(a) one substitutes the aboveobtained (5Z)-12β-formyl-6aβ,9β-methano derivative(5Z)-12β-formyl-9β-methyl-13,14,15,16,17,18,19,20-octanor-6a-carba-prostaglandinI₂ methyl ester, 11-tetrahydropyranyl ether and the procedure of Example3(a) through 3(d) is followed there is obtained(5Z)-6-aβ,9β-methano-15(R) and15(S)-16(R,S)-16-methyl-18,19-tetradehydro-6a-carba-prostaglandin I₂.

EXAMPLE 6

When in the procedure of Example 2(c) 2-hexynoic acid, or 5-hexenoicacid is substituted for 2-methyl-4-hexynoic acid one obtains2-oxo-hept-3-yne phosphonic acid dimethyl ester, and 2-oxo-hept-6-enephosphonic acid dimethyl ester.

EXAMPLE 7

When in the procedure of Example 3(a) one substitutes each of thephosphonic acid dimethyl ester compounds from Example 6 for3-methyl-2-oxohept-5-yne phosphonic acid dimethyl ester and(5Z)-12β-formyl-9β-methyl-13,14,15,16,17,18,19,20-octanor-6a-carba-prostaglandinI₂ methyl ester, 11-tetrahydropyranyl ether is substituted for thecorresponding (5E) isomer used in Example 3(a) and the procedure ofExample 3(a) through 3(d) is followed the following products areobtained:

(5Z)-9β-methyl-15(S)-16,17-tetradehydro-6a-carba-prostaglandin I₂ and

(5Z)-9β-methyl-15(S)-19,20-dehydro-6a-carba-prostaglandin I₂. ##STR32##

We claim:
 1. A compound of the formulawherein R is C₁ -C₄ alkyl; R₃₀ ishydrogen or R₃₀ and R taken together form a methylene moiety; wherein Dis cis>C═C(R₃)--, trans>C═C(R₃)-- or >CHCH₂, wherein R₃ is hydrogen orfluoro; wherein Z is:(1) --CH₂ --(CH₂)_(f) --C(R₄)₂ -- wherein each R₄is the same and is hydrogen or fluoro, and f is zero, one, 2 or 3; (2)trans--CH₂ --CH═CH--; or (3) --(PH)--(CH₂)_(g) -- wherein Ph is 1,2--,1,3--, or 1,4-phenylene and g is zero, one, 2 or 3; with the provisothat when Z is --(Ph)--(CH₂)_(g) --, R₃ is hydrogen; wherein Q is(1)--COOR₅, wherein R₅ is(a) hydrogen, (b) (C₁ -C₁₂)alkyl, (c) (C₃-C₁₀)cycloalkyl, (d) (C₇ -C₁₂)aralkyl, (e) phenyl optionally substitutedwith one, 2 or 3 chloro or (C₁ -C₄)alkyl, (f) phenyl substituted in thepara-position with --NHCOR₆, --COR₇, --OC(O)R₈ or --CH═N--NHCONH₂,wherein R₆ is methyl, phenyl, acetDamidophenyl, benzamidophenyl or --NH₂; R₇ is methyl, phenyl, --NH₂, or methoxy; and R₈ is phenyl oracetamidophenyl; (g) phthalidyl, (h)3-(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-yl P-oxide,(i)3-(5,5-di(hydroxymethyl)-1,3,2-dioxaphosphorinan-2-yl)-2-oxopropan-1-ylP-oxide, or (j) a pharmacologically acceptable cation; (2) --CH₂ OH; (3)--COL₂, wherein L₂ is(a) an amino group of the formula --NR₉ R₁₀ whereinR₉ is hydrogen or (C₁ --C₁₂)alkyl and R₁₀ is(i)hydrogen (ii) (C₁-C₁₂)alkyl (iii) (C₃ -C₁₀)cycloalkyl, (iv) (C₇ -C₁₂)aralkyl (v) phenyloptionally substituted with one, 2 or 3 chloro, (C₁ -C₃)alkyl, hydroxy,carboxy, (C₂ -C₅)alkoxycarbonyl, or nitro, (vi) (C₂ -C₅)carboxyalkyl,(vii) (C₂ -C₅)carbamoylalkyl, (viii) (C₂ -C₅)cyanoalkyl, (ix) (C₃-C₆)acetylalkyl, (x) (C₇ -C₁₂)benzoalkyl, optionally substituted by one,2, or 3 chloro, (C₁ -C₃)alkyl, hydroxy, (C₁ -C₃)alkoxy, carboxy, (C₂-C₅)-alkoxycarbonyl, or nitro, (ix) pyridyl, optionally substituted byone, 2, or 3 chloro, (C₁ -C₃)alkyl, or (C₁ -C₃)alkoxy, (xii) (C₆-C₉)pyridylalkyl optionally substituted by one, 2, or 3 chloro, (C₁-C₃)alkyl, hydroxy, or (C₁ -C₃)alkyl, (xiii) (C₁ -C₄)hydroxyalkyl, (xiv)(C₁ -C₄)dihydroxyalkyl, (xv) (C₁ -C₄)trihydroxyalkyl; (b) cycloamineselected from the group consisting of pyrolidino, piperidino,morpholino, piperazino, hexamethyleneimino, pyrroline, or3,4-didehydropiperidinyl optionally substituted by one or 2 (C₁-C₁₂)alkyl; (c) carbonylamino of the formula --NR₁₁ COR₁₀, wherein R₁₁is hydrogen or (C₁ -C₄)alkyl and R₁₀ is other than hydrogen, butotherwise defined as above; (d) sulfonylamino of the formula --NR₁₁ SO₂R₁₀, wherein R₁₁ and R₁₀ are defined in (c); (4) --CH₂ NL₃ L₄, whereinL₃ and L₄ are hydrogen or (C₁ -C₄)alkyl, being the same or different, orthe pharmacologically acceptable acid addition salts thereof when Q is--CH₂ NL₃ L₄ ; or (5) --CN; wherein L is H,H; α--OR₁₂,β--H; αH,β--OR₁₂ ;α--CH₂ OR₁₂,β--H; α--H,β--CH₂ OR₁₂ wherein R₁₂ is hydrogen or a hydroxylprotective group; wherein Y is trans --CH═CH--, cis--CH═CH--, --CH₂ CH₂--, or --C.tbd.C--; wherein M is α--OR₁₂,β--R₁₄ ; or α--R₁₄, β--OR₁₂,wherein R₁₂ is as defined above, and R₁₄ is hydrogen or methyl; whereinL₁ is α--R₁₅,β--R₁₆ ; α--R₁₆,β--R₁₅ ; or a mixture thereof wherein R₁₅and R₁₆ are hydrogen, methyl, or fluoro being the same or different withthe proviso that one of R₁₅ and R₁₆ is fluoro only when the other of R₁₅and R₁₆ is hydrogen or fluoro; wherein ##STR33## taken together is##STR34## (2) --C.tbd.C--C_(q) H_(2q) CH₃ where q is an integer of from2 to 6, and individual optical isomers thereof.
 2. A compound of claim 1wherein R₁₂ is hydrogen or a pharmacologically acceptable salt thereof.3. A compound of claim 2 wherein D is cis--C═C(R₃)-- ortrans--C═C(R₃)--.
 4. A compound of claim 3 wherein R₃ is hydrogen and Yis --CH₂ CH₂ --, --C.tbd.C-- or trans--CH.tbd.CH--.
 5. A compound ofclaim 4 wherein Z is --CH₂ (CH₂)_(f) --C(R₄)₂ -- and Q is --COOR₅ or--COL₂ wherein L₂ is --NR₉ R₁₀.
 6. A compound of claim 5 wherein##STR35##
 7. A compound of claim 6 wherein m is a α--OR₁₂,β--H.
 8. Acompound of claim 7 which is(5Z)-9β-methyl-15(S)-16(R,S)-16-methyl-18,19-tetradehydro-6a-carba-prostaglandinI₂.
 9. A compound of claim 6 which is(5Z)-9βmethyl-15(R)-16(R,S)-16-methyl-18,19-tetradehydro-6a-carba-prostaglandinI₂.